Shared neoantigens

ABSTRACT

Disclosed herein in one aspect is a pharmaceutical composition comprising a plurality of neoantigenic peptides and a pharmaceutically acceptable carrier, each neoantigenic peptide comprising a tumor-specific neoepitope capable of binding to an HLA protein in a subject, each tumor-specific neoepitope comprising a tumor-specific mutation present in a tumor, wherein (a) the composition comprises neoantigenic peptides comprising tumor-specific mutations present in at least 1% of subjects in a population of subjects suffering from cancer; (b) the composition comprises neoantigenic peptides comprising tumor-specific neoepitopes which bind to HLA proteins present in at least 5% of subjects in the population; and (c) the composition comprises at least one neoantigenic peptide capable of eliciting an immune response against a tumor present in at least 5% of the subjects in the population of subjects suffering from cancer.

RELATED APPLICATIONS AND INCORPORATION BY REFERENCE

This application is a § 371 of international patent application Serial No. PCT/US2016/033452 filed May 20, 2016, which published as PCT Publication No. WO 2016/187508 on Nov. 24, 2016, which claims priority and benefit of U.S. Provisional application Ser. No. 62/179,877 filed May 20, 2015 and U.S. Provisional application Ser. No. 62/389,377 filed Feb. 23, 2016.

The foregoing applications, and all documents cited therein or during their prosecution (“appln cited documents”) and all documents cited or referenced in the appln cited documents, and all documents cited or referenced herein (“herein cited documents”), and all documents cited or referenced in herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

SEQUENCE LISTING

The instant application contains a “lengthy” Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII format, created on Aug. 11, 2016, is named 47608_99_2007_SL.txt and is 10,252,288 bytes in size.

FIELD OF THE INVENTION

The present invention relates to methods and compositions for treating neoplasias, e.g. tumors, particularly using at least one neoantigenic peptide which is suitable for treating a significant proportion of subjects in a population suffering from cancer.

BACKGROUND OF THE INVENTION

Approximately 1.6 million Americans are diagnosed with neoplasia every year, and approximately 580,000 people in the United States are expected to die of the disease in 2013. Over the past few decades there been significant improvements in the detection, diagnosis, and treatment of neoplasia, which have significantly increased the survival rate for many types of neoplasia. However, only about 60% of people diagnosed with neoplasia are still alive 5 years after the onset of treatment, which makes neoplasia the second leading cause of death in the United States.

Currently, there are a number of different existing cancer therapies, including ablation techniques (e.g., surgical procedures, cryogenic/heat treatment, ultrasound, radiofrequency, and radiation) and chemical techniques (e.g., pharmaceutical agents, cytotoxic/chemotherapeutic agents, monoclonal antibodies, and various combinations thereof). Unfortunately, such therapies are frequently associated with serious risk, toxic side effects, and extremely high costs, as well as uncertain efficacy.

There is a growing interest in cancer therapies that seek to target cancerous cells with a patient's own immune system (e.g., cancer vaccines) because such therapies may mitigate/eliminate some of the herein-described disadvantages. Cancer vaccines are typically composed of tumor antigens and immunostimulatory molecules (e.g., cytokines or TLR ligands) that work together to induce antigen-specific cytotoxic T cells that target and destroy tumor cells. Current cancer vaccines may contain shared tumor antigens, which are native proteins (i.e.—proteins encoded by the DNA of all the normal cells in the individual) that are selectively expressed or over-expressed in tumors found in many individuals. While such shared tumor antigens are useful in identifying particular types of tumors, they are not ideal as immunogens for targeting a T-cell response to a particular tumor type because they are subject to the immune dampening effects of self-tolerance. Vaccines containing tumor-specific and patient-specific neoantigens can overcome some of the disadvantages of vaccines containing shared tumor antigens. However, the use of patient-specific neoantigens requires sequencing of individual subject's genomes, as well as the production of personalized compositions comprising a combination of neoantigens present in that individual subject. Accordingly, there is still a need for improved methods and compositions for delivering cancer vaccines.

Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.

SUMMARY OF THE INVENTION

Preferred statements (features) and embodiments of this invention are set herein below. Each statements and embodiments of the invention so defined may be combined with any other statement and/or embodiments unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features or statements indicated as being preferred or advantageous. Hereto, the present invention is in particular captured by any one or any combination of one or more of the below statements and embodiments, with any other statement and/or embodiments.

It is an objective of the invention to provide methods and compositions for the treatment of a population of cancer patients by eliciting an immune response targeting the cancer. In one aspect, the present invention relates to a pharmaceutical composition comprising at least one neoantigenic peptide and a pharmaceutically acceptable carrier, each at least one neoantigenic peptide comprising a tumor-specific neoepitope capable of binding to an HLA protein in a subject, each tumor-specific neoepitope comprising a tumor-specific mutation present in a tumor. The composition may include one neoantigenic peptide. In other embodiments, the composition may include more than 100 neoantigenic peptides. Preferably, the composition includes about 20 neoantigenic peptides. The at least one neoantigenic peptide may include a tumor-specific mutation. The mutation may be recurrent. Preferably, the mutation is present in a large proportion of a population. A recurrent mutation may be based on the mutation being present in a tumor in at least 1% of subjects in a population of subjects suffering from cancer. The composition may include at least one neoantigenic peptide containing a tumor-specific neoepitope which binds to an HLA protein present in at least 5% of subjects in the population of subjects suffering from cancer. Additionally, the composition may contain at least one neoantigenic peptide capable of eliciting an immune response against a tumor present in at least 5% of the subjects in the population of subjects suffering from cancer. The ability to elicit an immune response refers to the ability of the immune system to present an antigen to a lymphocyte. In order for the immune system to present an antigen, the antigen needs to be presented by a subjects HLA proteins. In order to elicit an immune response against a tumor, the tumor needs to contain the mutations leading to expression of the antigen. In order for the composition to provide a benefit to a population in need thereof, the population has to include subjects that express an HLA allele capable of binding the at least one neoantigenic peptide present in the composition and the population has to include subjects containing tumors with mutations that lead to neoantigenic epitopes present in the neoantigenic peptides.

The composition may be specific to a population of subjects suffering from cancer that share a characteristic. The population may have cancer or may have a specific cancer. The population may share a common set of HLA subtypes. They may share HLA subtypes based on ethnicity. Not being bound by a theory the percentage of HLA types in a population can be predicted based on ethnicity without testing. Not being bound by a theory, different populations express different HLA types capable of binding different neoantigenic peptides. Therefore a composition can be formulated to provide a benefit to a large proportion of that population, whereas the composition would not provide a benefit to another population. Not being bound by a theory, different cancers contain different mutations and thus compositions tailored to specific cancers can be used to provide a greater benefit to a population with one type of cancer as compared to a population that includes more than one type. In one embodiment, the population is suffering from adrenocortical carcinoma (ACC), bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), colon adenocarcinoma (COAD), Chronic lymphocytic Leukaemia (CLL), colorectal cancer (CRC), Diffuse large B-cell lymphoma (DLBCL), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), acute myeloid leukemia (LAML), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), multiple myeloma (MM), ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), testicular germ cell tumors (TGCT), thyroid adenocarcinoma (THCA), uterine corpus endometrioid carcinoma (UCEC), or uterine carcinosarcoma (UCS).

In one embodiment, the population of subjects is suffering from CLL; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “CLL”; and at least one of a set of six of the at least one tumor-specific mutation will be found in 17.49?% of subjects in the CLL population. The population of subjects may be suffering from BLCA, the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “BLCA”; and at least one of a set of six of the at least one tumor-specific mutation will be found in 26.92% of subjects in the population. The population of subjects may be suffering from BRCA; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “BRCA”; and at least one of a set of 18 of the at least one tumor-specific mutation will be found in 36.04% of subjects in the population. The population of subjects may be suffering from COAD; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “COAD”; and at least one of a set of three of the at least one tumor-specific mutation will be found in 27.14% of subjects in the population. The population of subjects may be suffering from GBM; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “GBM”; and at least one of a set of 14 of the at least one tumor-specific mutation will be found in 34.36% of subjects in the population. The population of subjects may be suffering from HNSC; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “HNSC”; and at least one of a set of 10 of the at least one tumor-specific mutation will be found in 21.61% of subjects in the population. The population of subjects may be suffering from KIRC; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “KIRC”; and at least one of a set of four of the at least one tumor-specific mutation will be found in 6% of subjects in the population. The population of subjects may be suffering from LAML; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “LAML”; and at least one of a set of 11 of the at least one tumor-specific mutation will be found in 47.45% of subjects in the population. The population of subjects may be suffering from LUAD; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “LUAD”; and at least one of a set of 11 of the at least one tumor-specific mutation will be found in 33.42% of subjects in the population. The population of subjects may be suffering from LUSC; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “LUSC”; and at least one of a set of two of the at least one tumor-specific mutation will be found in 7.87% of subjects in the population. The population of subjects may be suffering from OV; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “OV”; and at least one of a set of ten of the at least one tumor-specific mutation will be found in 22.78% of subjects in the population. The population of subjects may be suffering from READ; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “READ”; and at least one of a set of two of the at least one tumor-specific mutation will be found in 20.51% of subjects in the population. The population of subjects may be suffering from SKCM; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “SKCM”; and at least one of a set 64 of the at least one tumor-specific mutation will be found in 90.91% of subjects in the population. The population of subjects may be suffering from UCEC; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “UCEC”; and at least one of a set of 30 of the at least one tumor-specific mutation will be found in 67.74% of subjects in the population. The population of subjects may be suffering from ACC; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “ACC”; and at least one of a set of 161 of the at least one tumor-specific mutation will be found in 50% of subjects in the population. The population of subjects may be suffering from CESC; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “CESC”; and at least one of a set of four of the at least one tumor-specific mutation will be found in 23.71% of subjects in the population. The population of subjects may be suffering from CRC; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “CRC”; and at least one of a set of 15 of the at least one tumor-specific mutation will be found in 56.65% of subjects in the population. The population of subjects may be suffering from DLBCL; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “DLBCL”; and at least one of a set of 2 of the at least one tumor-specific mutation will be found in 13.79% of subjects in the population. The population of subjects may be suffering from KICH; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “KICH”; and at least one of a set of 24 of the at least one tumor-specific mutation will be found in 50% of subjects in the population. The population of subjects may be suffering from KIRP; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “KIRP”; and at least one of a set of nine of the at least one tumor-specific mutation will be found in 42.24% of subjects in the population. The population of subjects may be suffering from LIHC; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “LIHC”; and at least one of a set of 2 of the at least one tumor-specific mutation will be found in 6.57% of subjects in the population. The population of subjects may be suffering from MM; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “MM”; and at least one of a set of 6 of the at least one tumor-specific mutation will be found in 23.9% of subjects in the population. The population of subjects may be suffering from PRAD; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “PRAD”; and at least one of a set of 24 of the at least one tumor-specific mutation will be found in 39.85% of subjects in the population. The population of subjects may be suffering from STAD; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “STAD”; and at least one of a set of 150 of the at least one tumor-specific mutation will be found in 48.79% of subjects in the population. The population of subjects may be suffering from TGCT; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “TGCT”; and at least one of a set of 14 of the at least one tumor-specific mutation will be found in 51.61% of subjects in the population. The population of subjects may be suffering from THCA; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “THCA”; and at least one of a set of five of the at least one tumor-specific mutation will be found in 69.88% of subjects in the population. The population of subjects may be suffering from UCS; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “UCS”; and at least one of a set of two of the at least one tumor-specific mutation will be found in 16.07% of subjects in the population. The population of subjects may be suffering from PAAD; the at least one tumor-specific mutation comprises any combination of mutations in Table 8 with an exemplary disease of “PAAD”; and at least one of a set of 53 of the at least one tumor-specific mutation will be found in 50% of subjects in the population. The population of subjects may also be suffering from a solid tumor. The solid tumor may be clear cell Renal Cell Carcinoma (ccRCC), melanoma, sarcoma, or a cancer of the bladder, colon, brain, breast, head and neck, endometrium, lung, ovary, pancreas or prostate. The population of subjects may be suffering from a liquid tumor. The liquid tumor may be Non-Hodgkin's lymphoma or leukemia.

In another embodiment, the at least one tumor-specific mutation has an incidence of at least 500 patients a year in the population of subjects suffering from cancer, and wherein the at least one mutation may be a mutation listed for the population in Table 9. The at least one neoantigenic peptide may be at least one peptide listed in Table 9.

In another embodiment, the population suffering from cancer is being treated with a drug or therapy. The population suffering from cancer may have been previously treated with, is currently being treated with, or is selected to treated with ibrutinib, erlotinib, imatinib, gefitinib, crizotinib, trastuzumab, vemurafenib, RAF/MEK or antiestrogen therapy.

In another embodiment, the composition comprises at least one neoantigenic peptide capable of eliciting an immune response against a tumor present in at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99% of subjects in a population of subjects suffering from cancer.

In another embodiment, at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99% of subjects in the population has at least one tumor-specific mutation present in the composition; and at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99% of subjects in the population has at least one HLA protein which binds to a tumor-specific neoepitope present in the composition.

In one embodiment, the tumor-specific mutations comprise splice-variant mutations, point mutations, and/or frameshift mutations. In another embodiment, the tumor-specific mutations comprise drug resistance mutations. In one embodiment, the neoantigenic peptides include not only the resulting mutated neoantigen protein sequence, but a long peptide region surrounding and including the mutation and includes all contiguous segments within it (see Tables 1-4). In one embodiment, the tumor-specific mutations are present in one or more genes encoding a protein selected from the group consisting of Programmed Death-Ligand 1 (PD-L1), androgen receptor (AR), Bruton's Tyrosine Kinase (BTK), Epidermal Growth Factor Receptor (EGFR), BCR-Abl, c-kit, PIK3CA, HER2, EML4-ALK, KRAS, ALK, ROS1, AKT1, BRAF, MEKJ, MEK2, NRAS, RAC1, and ESR1. In one embodiment, the tumor-specific mutations are present in one or more genes listed in any of the Tables presented herein. In one embodiment, the at least one tumor-specific mutation is derived from alternative splicing of PD-L1 or AR. In one embodiment, the at least one tumor-specific mutation is derived from splice variant sPD-L1, AR-V1 or AR-V7. In one embodiment, the least one tumor-specific mutation is a drug resistance mutation selected from the group consisting of BTK/C481S, EGFR/T790M, BCR-Abl/T315I, BCR-Abl/Y253H, BCR-Abl/E255K, BCR-Abl/E255V, c-kit/T670L PIK3CA/E545K, PIK3CA/E542K, HER2/G776(YVMA), HER2/E545K, EML4-ALK/G1269A, KRAS/G12V/D, ALK/L196M, ALK/G1202R, ALK/S1206Y, ALK/1151T(ins), ALK/F1174C, ROS1/G2032R, AKT1/E17K, BRAF/V600E, MEK1/Q56P, MEK1/E203K, MEK1/C121S, MEK1/V60E, MEK1/G128V, MEK1/V54I, MEK1/P124S, MEK1/P124L, NRAS/Q61K/L/R, NRAS/T58I, MEK2/C125S, RAC1/P29S, ESR1/S463P, AR/V534E, AR/P535H, AR/L536Q, AR/L536R, AR/Y537C, AR/Y537S, AR/Y537N, AR/D538G and AR/F876L. In one embodiment, the drug resistance mutation is induced by treatment with ibrutinib, erlotinib, imatinib, gefitinib, crizotinib, trastuzumab, vemurafenib, RAF/MEK or antiestrogen therapy. In another embodiment, a subject has a drug resistance mutation before treatment.

In another embodiment, the composition comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 neoantigenic peptides. The composition may include 15 to 20 neoantigenic peptides. The composition may include greater than 100, 200, or 300 neoantigenic peptides. Each neoantigenic peptide may be from about 5 to about 50 amino acids in length.

In another embodiment, the pharmaceutical composition is an immunogenic or vaccine composition. The pharmaceutical composition may further comprise an immunomodulator or adjuvant. The immunodulator or adjuvant may be selected from the group consisting of poly-ICLC, 1018 ISS, aluminum salts, Amplivax, ASIS, BCG, CP-870,893, CpG7909, CyaA, cyclic di-nucleotides such as STING, dSLIM, GM-CSF, IC30, IC31, Imiquimod, ImuFact IMP321, IS Patch, ISS, ISCOMATRIX, Juvlmmune, LipoVac, MF59, monophosphoryllipid A, Montanide IMS 1312, Montanide ISA 206, Montanide ISA 50V, Montanide ISA-51, OK-432, OM-174, OM-197-MP-EC, ONTAK, PepTel®, vector system, PLGA microparticles, resiquimod, SRL172, Virosomes and other Virus-like particles, YF-17D, VEGF trap, R848, beta-glucan, Pam3Cys, and Aquila's QS21 stimulon.

In another embodiment, the pharmaceutical composition comprises one or more neoantigenic peptides as defined in Table 1, 2, 3 or 4.

In one embodiment, each tumor-specific neoepitope binds to HLA-A, -B or -C or to HLADRB, HLADBM XXXXX with a K_(D) of less than 500 nM.

In another aspect, the present invention relates to a method of treating or preventing a tumor in a subject in need thereof by administering to the subject any pharmaceutical composition as described herein.

In one embodiment, a method of treating or preventing a tumor in a patient in need thereof is provided, comprising administering to a patient a composition comprising at least one neoantigenic peptide and a pharmaceutically acceptable carrier, each at least one neoantigenic peptide comprising a tumor-specific neoepitope capable of binding to an HLA protein in a subject, each tumor-specific neoepitope comprising a tumor-specific mutation present in a tumor, wherein the composition comprises at least one neoantigenic peptide comprising a tumor-specific mutation present in a tumor in at least 1% of subjects in a population of subjects suffering from cancer; the composition comprises at least one neoantigenic peptide comprising a tumor-specific neoepitope which binds to an HLA protein present in at least 5% of subjects in the population of subjects suffering from cancer; and the composition comprises at least one neoantigenic peptide capable of eliciting an immune response against a tumor present in at least 5% of the subjects in the population of subjects suffering from cancer.

In one embodiment, the population of subjects is suffering from adrenocortical carcinoma (ACC), bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), colon adenocarcinoma (COAD), Chronic lymphocytic Leukaemia (CLL), colorectal cancer (CRC), Diffuse large B-cell lymphoma (DLBCL), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), acute myeloid leukemia (LAML), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), multiple myeloma (MM), ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), testicular germ cell tumors (TGCT), thyroid adenocarcinoma (THCA), uterine corpus endometrioid carcinoma (UCEC), or uterine carcinosarcoma (UCS). In one embodiment, the population of subjects is suffering from a solid tumor. The solid tumor may be clear cell Renal Cell Carcinoma (ccRCC), melanoma, sarcoma, or a cancer of the bladder, colon, brain, breast, head and neck, endometrium, lung, ovary, pancreas or prostate. In one embodiment, the population of subjects is suffering from a liquid tumor. The liquid tumor may be Non-Hodgkin's lymphoma or leukemia.

In one embodiment, the population suffering from cancer was treated with, is being treated with, or is selected to treated with ibrutinib, erlotinib, imatinib, gefitinib, crizotinib, trastuzumab, vemurafenib, RAF/MEK or antiestrogen therapy.

In one embodiment, the at least one neoantigenic peptide is capable of eliciting an immune response against a tumor present in at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99% of subjects in the population of subjects suffering from cancer. In one embodiment, at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99% of subjects in the population has at least one tumor-specific mutation present in the composition and, at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99% of subjects in the population has at least one HLA protein which binds to a tumor-specific neoepitope present in the composition.

In another embodiment, the tumor-specific mutations comprise splice-variant mutations, point mutations, and/or frameshift mutations. The tumor-specific mutations may be drug resistance mutations. The tumor-specific mutations may be present in one or more genes encoding a protein selected from the group consisting of Programmed Death-Ligand 1 (PD-L1), androgen receptor (AR), Bruton's Tyrosine Kinase (BTK), Epidermal Growth Factor Receptor (EGFR), BCR-Abl, c-kit, PIK3CA, HER2, EML4-ALK, KRAS, ALK, ROS1, AKT1, BRAF, MEK1, MEK2, NRAS, RAC1, and ESR1. The tumor-specific mutations may be present in one or more genes listed in any of the Tables. The at least one tumor-specific mutation may be derived from alternative splicing of PD-L1 or AR. The at least one tumor-specific mutation may be derived from splice variant sPD-L1, AR-V1 or AR-V7.

In one embodiment, the at least one tumor-specific mutation is a drug resistance mutation selected from the group consisting of BTK/C481S, EGFR/T790M, BCR-Abl/T315I, BCR-Abl/Y253H, BCR-Abl/E255K, BCR-Abl/E255V, c-kit/T670I, PIK3CA/E545K, PIK3CA/E542K, HER2/G776(YVMA), HER2/E545K, EML4-ALK/G1269A, KRAS/G12V/D, ALK/L196M, ALK/G1202R, ALK/S1206Y, ALK/I151T(ins), ALK/F174C, ROS1/G2032R, AKT1/E17K, BRAF/V600E, MEK1/Q56P, MEK1/E203K, MEK1/C121S, MEK1/V60E, MEK1/G128V, MEK1/V54I, MEK1/P124S, MEK1/P124L, NRAS/Q61K/L/R, NRAS/T58I, MEK2/C125S, RAC1/P29S, ESR1/S463P, AR/V534E, AR/P535H, AR/L536Q, AR/L536R, AR/Y537C, AR/Y537S, AR/Y537N, AR/D538G and AR/F876L. The drug resistance mutation may be induced by treatment with ibrutinib, erlotinib, imatinib, gefitinib, crizotinib, trastuzumab, vemurafenib, RAF/MEK or antiestrogen therapy.

In another embodiment, the composition comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 neoantigenic peptides. In a preferred embodiment, the composition comprises 15 to 20 neoantigenic peptides.

In another embodiment, each neoantigenic peptide is from about 5 to about 50 amino acids in length.

In another embodiment, the composition is an immunogenic or vaccine composition. For instance, the immunogenic or vaccine composition may comprise an immunomodulator or adjuvant. The immunodulator or adjuvant may be selected from the group consisting of poly-ICLC, 1018 ISS, aluminum salts, Amplivax, AS15, BCG, CP-870,893, CpG7909, CyaA, cyclic di-nucleotides such as STING, dSLIM, GM-CSF, IC30, IC31, Imiquimod, ImuFact IMP321, IS Patch, ISS, ISCOMATRIX, Juvlmmune, LipoVac, MF59, monophosphoryllipid A, Montanide IMS 1312, Montanide ISA 206, Montanide ISA 50V, Montanide ISA-51, OK-432, OM-174, OM-197-MP-EC, ONTAK, PepTel®, vector system, PLGA microparticles, resiquimod, SRL172, Virosomes and other Virus-like particles, YF-17D, VEGF trap, R848, beta-glucan, Pam3Cys, and Aquila's QS21 stimulon.

In one embodiment, the composition comprises one or more neoantigenic peptides as defined in Table 1, 2, 3 or 4.

In one embodiment, each tumor-specific neoepitope binds to HLA-A, -B or -C or to HLADRB, HLADBM XXXXX with a K_(D) of less than 500 nM.

In another aspect, the present invention provides a method of prophylactic cancer treatment comprising selecting a cancer drug for a patient in need thereof, the drug selected from the group consisting of ibrutinib, erlotinib, imatinib, gefitinib, crizotinib, trastuzumab, vemurafenib, RAF/MEK and antiestrogen therapy; and administering prophylactically to the subject, before drug resistant mutations can be detected, a pharmaceutical composition comprising neoantigenic peptides derived from drug resistant mutations associated with the selected cancer drug.

The shared neoantigen immunogenic composition can be administered via subcompositions, each containing a portion of the neoantigens, and sub-compositions can be administered to different places on the subject or patient; for instance, a composition comprising 20 different neoantigens, can be administered in four (4) subcompositions, each containing 5 of the 20 different neoantigens, and the four (4) subcompositions can be administered so as to endeavor to deliver each subcomposition to a separate set of draining lymph nodes of the patient, e.g., to each of the arms and legs (e.g., thigh or upper thigh or near buttocks or lower back on each side of the patient) so as to endeavor to deliver fewer neoantigens to each set of draining lymph nodes of the patient or subject and thereby limit competition between neoantigens. Of course, the number of locations and hence number of subcompositions can vary, e.g., the skilled practitioner could consider administration at or near the spleen to have a fifth point of administration, and the skilled practitioner can vary the locations such that only one, two or three are used (e.g., each arm and a leg, each of legs and one arm, each of the legs and no arms, or only both arms). The shared neoantigen immunogenic composition administered at the aforementioned various intervals can be different formulations, and the subcompositions administered at different places on the subject or patient during a single administration can be different compositions. For instance, a first administration can be of a whole shared neoantigen immunogenic composition and a next or later administration can be of a vector (e.g., viral vector or plasmid) that has expression of antigen(s) in vivo. Likewise, in the administration of different subcompositions to different locations on the patient or subject, some of the subcompositions can comprise a whole antigen and some of the subcompositions can comprise a vector (e.g., viral vector or plasmid) that has expression of antigen(s) in vivo. And some compositions and subcompositions can comprise both vector(s) (e.g., viral vector or plasmid) that has/have expression of antigen(s) in vivo and whole antigens. Some vectors (e.g., poxvirus) that have expression of antigen(s) in vivo can have an immunostimulatory or adjuvanting effect, and hence compositions or subcompositions that contain such vectors can be self-adjuvanting. Also, by changing up the nature of how the antigens are presented to the immune system, the administrations can “prime” and then “boost” the immune system. And in this text, when there is mention of a “vaccine” it is intended that the invention comprehends immunogenic compositions, and when there is mention of a patient or subject it is intended that such an individual is a patient or subject in need of the herein disclosed treatments, administrations, compositions, and generally the subject invention.

Moreover, the invention applies to the use of any type of expression vector, such as a viral expression vector, e.g., poxvirus (e.g., orthopoxvirus or avipoxvirus such as vaccinia virus, including Modified Vaccinia Ankara or MVA, MVA-BN, NYVAC according to WO-A-92/15672, fowlpox, e.g., TROVAX, canarypox, e.g., ALVAC (WO-A-95/27780 and WO-A-92/15672) pigeonpox, swinepox and the like), adenovirus, AAV, herpesvirus, and lentivirus; or a plasmid or DNA or nucleic acid molecule vector. Some vectors that are cytoplasmic, such as poxvirus vectors, may be advantageous. However adenovirus, AAV and lentivirus can also be advantageous to use in the practice of the invention.

In a ready-for-use, especially reconstituted, shared neoantigen immunogenic composition, the vector, e.g., viral vector, is present in the quantities within the ambit of the skilled person from this disclosure and the knowledge in the art (such as in patent and scientific literature cited herein).

Whole antigen or vector, e.g., recombinant live vaccines may exist in a freeze-dried form allowing their storage and are reconstituted immediately before use in a solvent or excipient, which can include an adjuvant as herein discussed.

The subject of the invention is therefore also a vaccination or immunization set or kit comprising, packaged separately, freeze-dried vaccine and a solution, advantageously including an adjuvant compound as herein discussed for the reconstitution of the freeze-dried vaccine.

The subject of the invention is also a method of vaccination or immunization comprising or consisting essentially of or consisting of administering, e.g., by the parenteral, preferably subcutaneous, intramuscular or intradermal, route or by the mucosal route a vaccine or immunogenic composition in accordance with the invention at the rate of one or more administrations. Optionally this method includes a preliminary step of reconstituting the freeze-dried shared neoantigen immunogenic composition (e.g., if lyophilized whole antigen or vector) in a solution, advantageously also including an adjuvant.

In one embodiment, the shared neoantigen immunogenic composition is administered at a dose of about 10 μg to 1 mg per 70 kg individual as to each neoantigenic peptide. In another embodiment, the shared neoantigen immunogenic composition is administered at an average weekly dose level of about 10 μg to 2000 μg per 70 kg individual as to each neoantigenic peptide. In another related embodiment, the administration is intravenous. In one embodiment, the shared neoantigen immunogenic composition is administered intravenously or subcutaneously.

In another embodiment, the method further comprises (a) obtaining a sample of tumor tissue from each subject; (b) detecting one or more of the tumor-specific mutations in the sample; and (c) selecting a subject from the population of subjects for treatment with the at least one neoantigenic peptides if at least one of the tumor-specific mutations are detected in the sample from the subject.

In another embodiment, the method further comprises (a) determining HLA allotypes present in each subject; and (b) selecting a subject from the population of subjects for treatment with the at least one neoantigenic peptides if one or more HLA allotypes present in the subject binds to one or more of the tumor-specific neoepitopes present in the at least one neoantigenic peptides.

Embodiments of the present invention relate to compositions and methods using shared neoantigens, which (unlike shared native (non-mutated) antigens derived from genes differentially expressed in tumors) have desirable properties such as not being subject to the immune-dampening effects of central tolerance and high tumor specificity. This is because the neoantigens are expressed only in tumor tissue, e.g. are generated by tumor-specific mutations or splicing defects. Such splice variants or mutations may generate immunogenic epitopes across a variety of HLA alleles, thus covering a significant proportion of the population. Moreover, because these mutations may be present in a significant proportion of subjects suffering from cancer, the compositions described herein do not require sequencing of whole genomes of subjects and may be used as an “off-the-shelf” product to treat multiple subjects. For instance, the method may simply involve detecting in a tumor sample from the subject one or more of the specific mutations present in the composition, and administering the composition to subjects in which at least one mutation is present. This is in contrast to methods using patient-specific neoantigen mixtures, which require whole genome or whole exome sequencing of each subject and the production of personalized treatment compositions.

Other embodiments relate to a combination therapy wherein the methods of treatment using a shared neoantigen composition of the present invention are used in concert with a current drug regimen. The shared neoantigen composition may be administered prophylactically. In one embodiment, a patient in need thereof is treated with chemotherapy and/or a targeted therapy in combination with a shared neoantigen immunogenic composition before a drug resistance mutation can be detected. The shared neoantigen immunogenic composition can be tailored to include neoantigen peptides specific to the resistance mutations associated with a chosen therapy. In another embodiment, the shared neoantigen composition is administered before the subject is treated with a chemotherapy and/or a targeted therapy, to generate an immune response to cells harboring a drug resistance mutation before such cells develop. The administering can be serially or sequentially or at substantially the same time or substantially simultaneously. For example, the administering of the shared neoantigen immunogenic composition and the administering of a cancer therapy can be at about the same time or substantially simultaneously. Alternatively, the administering of the shared neoantigen immunogenic composition can be on one time schedule, e.g., weekly, biweekly, every three weeks, monthly, bimonthly, every quarter year (every three months), every third of a year (every four months), every five months, twice yearly (every six months), every seven months, every eight months, every nine months, every ten months, every eleven months, annually or the like, and the administering of the cancer therapy can be on a different schedule that is typical for the therapy such that the subject or patient has two different treatment schedules running concomitantly and the administering of the shared neoantigen immunogenic composition and the administering of the cancer therapy can be sequentially or serially. In preferred embodiments the subject may be treated with ibrutinib, erlotinib, imatinib, gefitinib, crizotinib, trastuzumab, vemurafenib, RAF/MEK or antiestrogen therapy.

In another aspect the present invention provides a diagnostic method for early detection and tracking of cancer progression by determining the presence of at least one neoantigenic peptide of the present invention in a patient sample. The patient sample may be derived from blood, sputum, saliva, urine, tumor tissue, lymphatic fluid, semen or feces.

In one embodiment, the diagnostic method is used before administering the shared neoantigen composition as described herein. The diagnostic method may include comparing the amount of shared neoantigen mutations in a series of at least two samples taken during treatment with a cancer therapy and/or shared neoantigen composition. Not being bound by a theory, an increase or decrease in shared neoantigen mutations can be used to determine treatment efficacy.

In one embodiment, the mutated genes can be detected using PCR based methods or sequencing. Reverse transcription PCR (RT-PCR) can be used to detect mutations in transcribed neoantigen genes. Additionally, any sequencing technique can be used to determine the presence of a mutation. In a preferred embodiment, pyrosequencing is used. The present invention also provides for a kit that includes primers that are specific to sequences encompassing the neoantigen mutations.

In another embodiment the mutated genes are detected by immunological detection methods. Antibodies specific to the shared neoantigen mutations can be used to detect the mutations. The antibodies may be bound to an array. The array may include antibodies to detect more than one of the shared neoantigen mutations of the present invention. The antibodies can be configured for use in an ELISA assay. Therefore, a composition or kit may be provided that includes antibodies specifically recognizing the shared neoantigens of the present invention.

In another aspect the present invention provides a method of treating or preventing a tumor in a population of subjects in need thereof, comprising administering to a subject an agent comprising an extracellular ligand-binding domain recognizing a tumor-specific neoepitope comprising a tumor-specific mutation having an incidence of at least 1% of subjects in the population. The agent may be an antibody, antibody fragment, antibody drug conjugate, aptamer, CAR, or T cell receptor. The antibody or antibody fragment may be humanized, fully humanized, or chimeric. The antibody fragment may be a nanobody, Fab, Fab′, (Fab′)2, Fv, ScFv, diabody, triabody, tetrabody, Bis-scFv, minibody, Fab2, or Fab3 fragment. The tumor-specific mutation may be a mutation listed for any population in Table 9. The tumor-specific mutation may be within a gene containing an extracellular domain. The tumor-specific mutation may be FGFR3 S249C, ERBB3 V104M, EGFR L858R, MUC4 H4205Q, PDGFRA R483fs, TMEM52 23_26LLPL>L, or PODXL 28_30PSP>P. The tumor-specific mutation may be within the extracellular domain. The tumor-specific mutation comprises FGFR3 S249C or ERBB3 V104M. Not being bound by a theory, the presence of a neoepitope in a protein with an extracellular domain allows the neoepitope to be presented on the surface of a cell. Not being bound by a theory, the presence of a neoepitope in the extracellular domain allows the neoepitope to be presented on the surface of a cell.

The invention is further described by the following numbered paragraphs:

1. An isolated neoantigenic peptide comprising a tumor-specific neoepitope defined in Tables 1-9, wherein the isolated neoantigenic peptide is not a native polypeptide.

2. An isolated neoantigenic peptide 100 amino acids or less in length which comprises a tumor-specific neoepitope defined in Tables 1-9.

3. The isolated neoantigenic peptide of paragraph 1 or 2, which is between about 5 to about 50 amino acids in length.

4. The isolated neoantigenic peptide of any of paragraphs 1-3, which is between about 15 to about 35 amino acids in length.

5. The isolated neoantigenic peptide of paragraph 4, which is about 15 amino acids or less in length.

6. The isolated neoantigenic peptide of paragraph 5, which is between about 8 and about 11 amino acids in length.

7. The isolated neoantigenic peptide of paragraph 6, which is 9 or 10 amino acids in length.

8. The isolated neoantigenic peptide of any of paragraphs 1-7, which binds major histocompatibility complex (MHC) class I.

9. The isolated neoantigenic peptide of paragraph 8, which binds MHC class I with a binding affinity of less than about 500 nM.

10. The isolated neoantigenic peptide of any of paragraphs 1-3, which is about 30 amino acids or less in length.

11. The isolated neoantigenic peptide of paragraph 10, which is between about 6 and about 25 amino acids in length.

12. The isolated neoantigenic peptide of paragraph 11, which is between about 15 and about 24 amino acids in length.

13. The isolated neoantigenic peptide of paragraph 11, which is between about 9 and about 15 amino acids in length.

14. The isolated neoantigenic peptide of any of paragraphs 1-3 and 10-13, which binds MHC class II.

15. The isolated neoantigenic peptide of paragraph 14, which binds MHC class II with a binding affinity of less than about 1000 nM.

16. The isolated neoantigenic peptide of any of paragraphs 1-15, further comprising flanking amino acids.

17. The isolated neoantigenic peptide of paragraph 16, wherein the flanking amino acids are not native flanking amino acids.

18. The isolated neoantigenic peptide of any of paragraphs 1-17, which is linked to at least a second neoantigenic peptide.

19. The isolated neoantigenic peptide of paragraph 18, wherein peptides are linked using a poly-glycine or poly-serine linker.

20. The isolated neoantigenic peptide of paragraph 18 or 19, wherein the second neoantigenic peptide binds MHC class I or class II with a binding affinity of less than about 1000 nM.

21. The isolated neoantigenic peptide of paragraph 20, wherein the second neoantigenic peptide binds MHC class I or class II with a binding affinity of less than about 500 nM.

22. The isolated neoantigenic peptide of paragraph 20 or 21, wherein both of the neoepitopes bind to human leukocyte antigen (HLA)-A, -B, -C, -DP, -DQ, or -DR.

23. The isolated neoantigenic peptide of any of paragraphs 20-22, wherein the isolated neoantigenic peptide and the second neoantigenic peptide binds a class I HLA or the isolated neoantigenic peptide and the second neoantigenic peptide binds a class II HLA.

24. The isolated neoantigenic peptide of any of paragraphs 20-22, wherein the isolated neoantigenic peptide binds a class II HLA and the second neoantigenic peptide binds a class I HLA or the isolated neoantigenic peptide binds a class I HLA and the second neoantigenic peptide binds a class II HLA.

25. The isolated neoantigenic peptide of any of paragraphs 1-24, further comprising modifications which increase in vivo half-life, cellular targeting, antigen uptake, antigen processing, MHC affinity, MHC stability, or antigen presentation.

26. The isolated neoantigenic peptide of paragraph 25, wherein the modification is conjugation to a carrier protein, conjugation to a ligand, conjugation to an antibody, PEGylation, polysialylation HESylation, recombinant PEG mimetics, Fc fusion, albumin fusion, nanoparticle attachment, nanoparticulate encapsulation, cholesterol fusion, iron fusion, acylation, amidation, glycosylation, side chain oxidation, phosphorylation, biotinylation, the addition of a surface active material, the addition of amino acid mimetics, or the addition of unnatural amino acids.

27. The isolated neoantigenic peptide of paragraph 25, wherein the cells that are targeted are antigen presenting cells.

28. The isolated neoantigenic peptide of paragraph 27, wherein the antigen presenting cells are dendritic cells.

29. The isolated neoantigenic peptide of paragraph 29, wherein the dendritic cells are targeted using the CD141, DEC205, or XCR1 marker.

30. A pharmaceutical composition comprising at least one neoantigenic peptide and a pharmaceutically acceptable carrier, each at least one neoantigenic peptide comprising a tumor-specific neoepitope capable of binding to an HLA protein in a subject, each tumor-specific neoepitope comprising a tumor-specific mutation present in a tumor, wherein:

-   -   (a) the composition comprises at least one neoantigenic peptide         comprising a tumor-specific mutation present in a tumor in at         least 1% of subjects in a population of subjects suffering from         cancer;     -   (b) the composition comprises at least one neoantigenic peptide         comprising a tumor-specific neoepitope which binds to an HLA         protein present in at least 5% of subjects in the population of         subjects suffering from cancer; or     -   (c) the composition comprises at least one neoantigenic peptide         capable of eliciting an immune response against a tumor present         in at least 5% of the subjects in the population of subjects         suffering from cancer.

31. The pharmaceutical composition of paragraph 30, wherein the population of subjects is suffering from adrenocortical carcinoma (ACC), bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), colon adenocarcinoma (COAD), Chronic lymphocytic Leukaemia (CLL), colorectal cancer (CRC), Diffuse large B-cell lymphoma (DLBCL), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), acute myeloid leukemia (LAML), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), multiple myeloma (MM), ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), testicular germ cell tumors (TGCT), thyroid adenocarcinoma (THCA), uterine corpus endometrioid carcinoma (UCEC), or uterine carcinosarcoma (UCS).

32. The pharmaceutical composition of paragraph 30 or 31, wherein the population suffering from cancer was treated with, is being treated with, or is selected to be treated with a cancer therapeutic, optionally ibrutinib, erlotinib, imatinib, gefitinib, crizotinib, trastuzumab, vemurafenib, RAF/MEK inhibitor or antiestrogen therapy.

33. The pharmaceutical composition of any of paragraphs 30-33, wherein the tumor-specific mutations comprise splice-variant mutations, point mutations, and/or frameshift mutations.

34. The pharmaceutical composition of any of paragraphs 30-33, wherein the at least one neoantigenic peptide comprises at least one neoantigenic peptide derived from a long peptide region flanking and including the tumor specific mutation, and wherein all contiguous segments within the long peptide are included.

35. The pharmaceutical composition of any of paragraphs 30-34, wherein the tumor-specific mutations are present in one or more genes listed in Tables 1-9.

36. The pharmaceutical composition of any of paragraphs 30-35, wherein the composition comprises at least one neoantigenic peptide as defined in any of Tables 1-9.

37. The pharmaceutical composition of any of paragraphs 30-36, wherein the tumor-specific mutations are present in one or more genes encoding a protein selected from the group consisting of Programmed Death-Ligand 1 (PD-L1), androgen receptor (AR), Bruton's Tyrosine Kinase (BTK), Epidermal Growth Factor Receptor (EGFR), BCR-Abl, c-kit, PIK3CA, HER2, EML4A-ALK, KRAS, ALK, ROS1, AKT1, BRAF, MEK1, MEK2, NRAS, RAC1, and ESR1.

38. The pharmaceutical composition of paragraph 37, wherein at least one tumor-specific mutation is derived from alternative splicing of PD-L1 or AR.

39. The pharmaceutical composition of paragraph 38, wherein at least one tumor-specific mutation is derived from splice variant sPD-L1, AR-V1 or AR-V7.

40. The pharmaceutical composition of any of paragraphs 30-39, wherein the tumor-specific mutations comprise drug resistance mutations.

41. The pharmaceutical composition of paragraph 40, wherein at least one tumor-specific mutation is a drug resistance mutation selected from the group consisting of BTK/C481S, EGFR/T790M, BCR-Abl/T315I, BCR-Abl/Y253H, BCR-Abl/E255K, BCR-Abl/E255V, c-kit/T670I, PIK3CA/E545K, PIK3CA/E542K, HER2/G776(YVMA), HER2/E545K, EML4-ALK/G1269A, KRAS/G12V/D, ALK/L1196M, ALK/G1202R, ALK/S1206Y, ALK/1151T(ins), ALK/F1174C, ROS1/G2032R, AKT1/E17K, BRAF/V600E, MEK1/Q56P, MEK1/E203K, MEK1/C121S, MEK1/V60E, MEK1/G128V, MEK1/V154I, MEK1/P124S, MEK1/P124L, NRAS/Q61K/L/R, NRAS/T58I, MEK2/C125S, RAC1/P29S, ESR1/S463P, AR/V534E, AR/P535H, AR/L536Q, AR/L536R, AR/Y537C, AR/Y537S, AR/Y537N, AR/D538G and AR/F876L.

42. The pharmaceutical composition of any of paragraphs 30-41, wherein the at least one tumor-specific mutation has an incidence of at least 500 patients a year in the population of subjects suffering from cancer, and wherein the at least one mutation comprises a mutation listed for the population in Table 9.

43. The pharmaceutical composition of paragraph 42, wherein the at least one neoantigenic peptide comprises at least one peptide listed in Table 9.

44. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from CLL; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         SF3B1:p.K700E, MYD88:p.L273P, NOTCH1:p.P2514fs, ABCA11P:p.E901D,         AHNAK:p.D3823E, ZNF814:p.E348D, AHNAK:p.V1220I, AHNAK:p.H1203N,         ANKRD30A:p.A232V, APOOL:p.138L, EGR2:p.H397N, MKI67:p.H2213D,         NRAS:p.Q61R, PLIN4:p.M691V, XPO1:p.E571K, ZCRB1:p.L76F,         ZNF700:p.N652H, ZNF700:p.Q654R, ZNF844:p.D458H, AHNAK:p.A4046V,         ANKRD36:p.P337R, C1orf170:p.T203I, CAST:p.D639E, EGR2:p.E369K,         GPR123:p.L630P, IKZF3:p.L162R, MUC4:p.P4224R, OR9Q1:p.M34L,         PKD2:p.Y486F, PRAMEF11:p.R104Q, SYNJ1:p.I681F, TP53:p.R248Q,         TP53:p.R248W, TRPV2:p.L627del, ZNF254:p.S498A, ZNF732:p.A459T,         ZNF749:p.E530Q, ZNF845:p.M423I, ABCA11P:p.G900E, ACRC:p.E243D,         ACRC:p.A244V, ACSL3:p.T188S, ADAMTS2:p.D948N, AGAP6:p.S127L         AHNAK:p.A2114G, ANKRD36:p.D1014Y, ARID3A:p.G550fs,         ARID4A:p.D1154E, ATP2B4:p.R183H, ATRNL1:p.L1244F, BNC1:p.Y937N,         BRAF:p.K601N, BTLA:p.Q86K, C14orf177:p.G90V, C2orf44:p.N456K,         C3orf15:p.R552Q, CACNA2D1:p.Y376N, CALD1:p.E340K,         CCDC15:p.P488H, CCDC79:p.N440T, CCNB3:p.A932T, CD109:p.L470Q,         CD209:p.Q189L, CKAP2:p.*684K, CMA1:p.I81K, CMIP:p.A230T,         CNTNAP4:p.112F, CRYM:p.*315K, DICER1:p.E1705K, DPCR1:p.L716P,         EIF3A:p.M1093L, EIF4G3:p.R8H, ETFDH:p.I281F, EWSR1:p.Y656C,         F5:p.L1332P, F5:p.L1253F, FAM50A:p.H317R, FBXL13:p.S102R,         FBXW7:p.R465H, FHL:p.D184E, FILIP1:p.1522K, FRG1B:p.Q39K,         GNB1:p.I80T, GPR110:p.R443G, GPR98:p.Y6152F,         HDGFL1:p.188_189insA, IGF2BP2:p.T186S, IL1R2:p.L364fs,         KIAA1109:p.L4680P, KRAS:p.G13D, KRTAP19-1:p.G61 S, MAF:p.G53fs,         MAGEC1:p.L609H, MAP2K1:p.K57N, MED12:p.L36R, MED12:p.G44S,         METAP2:p.Y137N, METTL9:p.Y57F, MGP:p.V15L, MKI67:p.R2222K,         MUC16:p.T11005I, MUC4:p.S3941N, MUC4:p.S3941G, MUC4:p.V3091L,         MUC4:p.S2951Y, MUC4:p.A2841S, MUC4:p.S2760A, MUC4:p.T2335M,         MUC4:p.T1627K, MUC4:p.T1547S, MUC4:p.H1133Q, MYD88:p.M240T,         NEDD4L:p.P194del, NEFH:p.S704T, NRG4:p.G21fs, OR2A25:p.S105C,         OR4C16:p.Y63F, OR4N4:p.L150fs, PABPC1:p.K254fs, PIWIL1:p.P372fs,         PLCD3:p.E499fs, PLEKHB1:p.S146P, PPIL4:p.S382R, PRDM4:p.*802K,         PRG4:p.N675H, PRKAB1:p.P104H, R3HDM2:p.S592G, R3HDM2:p.S588N,         R3HDM2:p.R206W, RPS2:p.R200G, RPTN:p.G364S, SF3B1:p.K666E,         SF3B1:p.N626Y, SF3B1:p.Y623C, SIX3:p.I27L, SLC39A7:p.L456fs,         SLC6A9:p.R94K, TFG:p.A382V, TGOLN2:p.K83R, TGOLN2:p.T80S,         TLR2:p.D327V, TNKS2:p.T619fs, TP53:p.R273H, TP53:p.C242F,         TP53:p.R175H, TWISTNB:p.H306Q, UBXN7:p.A276V, WDR78:p.N110K,         XIRP2:p.V3008E, ZNF382:p.H186Q, ZNF578:p.R306H, ZNF578:p.G311S,         ZNF578:p.H334R, ZNF700:p.S649C, ZNF705A:p.D298N, ZNF836:p.K608Q,         and ZNF836:p.I571N; and

45. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from BLCA; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         PIK3CA:p.E545K, FGFR3:p.S249C, TP53:p.R248Q, PIK3CA:p.E542K,         RXRA:p.S427F, ZNF814:p.D404E, FBXW7:p.R505G, NOTCH2:p.P6fs,         TP53:p.E285K, ANKRD30A:p.A353P, C3orf70:p.S6L, EFCAB6:p.R379K,         ERCC2:p.N238S, FAM47C:p.Q225E, FOXQ1:p.S135L, HLA-A:p.Q78R,         MUC4:p.H4205Q, OTUD4:p.T909I, SLAMF1:p.S277fs, SPRED3:p.S128del,         TMCO2:p.S15fs, TP53:p.R280T, TP53:p.E271K, TP53:p.A159V,         ZNF706:p.I8N, ZNF706:p.R3P, ACACB:p.E2318Q, ACPP:p.E321K,         ACRC:p.A264V, ADAMTS2:p.23_24insL, AFF3:p.E919K, AHNAK:p.S4150F,         AHNAK:p.D2889H, AHNAK:p.V1940A, ALX4:p.R126Q, ANKRD12:p.E627K,         ANKRD32:p.T999N, ARID1A:p.S614L, ASXL2:p.117_118SS>S,         ATP12A:p.R858C, ATP9A:p.R519Q, BCAS3:p.T214M, BPI:p.M255I,         CACNG8:p.V146G, CAMSAP1:p.T466fs, CDC27:p.I91fs, CDKN1A:p.E44fs,         CEP192:p.S2058L, CGB8:p.T18A, CHRNA3:p.L23del, CHST4:p.D352N,         CLIP 1:p.S018fs, COX6A1:p.S8L, CREBBP:p.D1435H, CRIPAK:p.M48fs,         CSPG5:p.D119N, CUL1:p.E485K, DLC1:p.S741T, DLL3:p.D318H,         DOPEY2:p.E1196K, ECM1:p.E266K, EEF1A2:p.Y418S, EEF2K:p.E673K,         EMILIN1:p.R27G, ERBB2:p.S310F, ERBB3:p.M91I, ERBB3:p.V104L,         ERBB3:p.D297Y, ERCC2:p.Y14C, FAM155A:p.Q86del, FAM43B:p.E272del,         FASTKD3:p.Q625E, FBXW7:p.S546L, FGFR3:p.R248C, FGFR3:p.G380R,         FGFRL1:p.H479fs, GBE1:p.M587I, GIMAP1-GIMAP5:p.S311C,         GNA13:p.R200G, HiFOO:p.A214fs, HEATR7B2:p.E1109K,         HISTIHID:p.I81M, HRAS:p.G12D, HRCT1:p.H92P, ILF3:p.E484K,         KCNK2:p.S6W, KIAA0907:p.Q446P, KIF23:p.E350K, KLF5:p.S118L,         KLHL15:p.D185G, LAMA4:p.E639K, LILRA1:p.H410Y, LILRB1:p.L479del,         LLGL2:p.P955fs, LPIN1:p.S974L, LRRC16A:p.D227N, LRTM2:p.S139L,         LURAP1L:p.55_56insGGG, MAGEC1:p.P553del, MCL1:p.E171del,         MN1:p.S472L, MUC7:p.A191V, MVP:p.E412K, NBPF10:p.E3455K,         NFE2L2:p.E79K, NFE2L2:p.R34G, NOS1AP:p.Q306del, OR2T35:p.V319fs,         OR4N2:p.L150fs, PABPC3:p.K333fs, PAX3:p.S197L, PBX2:p.E70K,         PBXIP1:p.H729del, PCDP1:p.E537K, PEX1:p.I370fs, PHLDA3:p.E82K,         PLEKHM2:p.S459L, PLVAP:p.A321V, POLR3B:p.L372F, POTEC:p.R477Q,         PPL:p.H326Y, PPP1R15A:p.E196K, PRDM16:p.E271Q, PRIC285:p.E1289Q,         PRMT8:p.S31P, PUF60:p.S396L, RAB11FIP4:p.S596L, RAD51C:p.D167N,         RAD51C:p.Y224H, RALGPS1:p.R381Q, RARS2:p.R6C, RBM26:p.P644A,         RERE:p.K176N, RXRA:p.S427Y, SERPINA12:p.R211G, SF3B1:p.E902K,         SLC6A9:p.R243W, SLC9A5:p.L447F, SPESP1:p.F121L, SRPRB:p.G14S,         SYN2:p.A34del, SYTL2:p.I440M, TAB3:p.R211T, TAF1B:p.R292C,         TAOK2:p.L981del, TAS1R3:p.E525K, TAS2R9:p.E163Q, TBC1D1:p.S71F,         TBC1D2B:p.R920Q, TFPI2:p.R222C, TM6SF1:p.S15W, TMEM131:p.K640fs,         TMEM19:p.G331fs, TP53:p.R273C, TP53:p.R248W, TP53:p.R175H,         TP53:p.K132N, TRAM1:p.E41Q, TSKS:p.E513K, TTN:p.C20935G,         UBOX5:p.S417L, UGP2:p.D262H, VGF:p.E433K, XAB2:p.E782K,         XYLB:p.S87F, ZC3H4:p.E798K, ZNF208:p.K852E, ZNF208:p.I647S,         ZNF626:p.G198E, ZNF749:p.Q457E, ZNF761:p.H373R, ZNF799:p.T43A,         ZNF799:p.W41G, ZNF799:p.E589G, ZNF844:p.P503R, ZNF845:p.M423T,         ZNF845:p.T479M, ZNF860:p.H464R, ZNF878:p.S181R, ZNF91:p.R333H,         and ZNF91:p.H305R.

46. The pharmaceutical composition of any of paragraphs 30-43, wherein:

-   -   (a) the population of subjects is suffering from BRCA; and     -   (b) the at least one tumor-specific mutation comprises any         combination of frameshift mutations selected from the group         consisting of GATA3:p.L328fs, GATA3:p.N334fs, GATA3:p.L344fs,         GATA3:p.H400fs, GATA3:p.S408fs, GATA3:p.S430fs, GATA3:p.H434fs,         GATA3:p.H435fs, and GATA3:p.S408fs.

47. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from BRCA; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         PIK3CA:p.H1047R, PIK3CA:p.E545K, PIK3CA:p.E542K, AKT1:p.E17K,         TP53:p.R175H, PIK3CA:p.N345K, PIK3CA:p.H1047L, SF3B1:p.K700E,         GATA3:p.S408fs, PIK3CA:p.E726K, TP53:p.Y220C, TP53:p.H193R,         PIK3CA:p.Q546R, TP53:p.R273C, TP53:p.R248W, TP53:p.R273H,         TP53:p.I195T, TP53:p.H179R, FGFR2:p.N549K, NUP93:p.E14K,         PIK3CA:p.C420R, PIK3CA:p.E453K, PIK3CA:p.Q546K, TP53:p.V216M,         TP53:p.C176F, CDH1:p.E243K, ERBB2:p.L755S, KRAS:p.G12V,         PIK3CA:p.E545A, TBL1XR1:p.I141fs, TP53:p.G266E, TP53:p.R248Q,         TP53:p.Y163C, TP53:p.C141Y, TP53:p.G108fs, ACPP:p.R43W,         AKT2:p.I289M, ARHGAP9:p.R137C, C9orf174:p.R136W,         CDC42BPA:p.P675T, COL12A1:p.S395L, CRISPLD1:p.R222W,         CT47B1:p.234_243EKLTEEATEE>E, CYP1A2:p.V483M, DAB2IP:p.E161K,         DGKB:p.S13L, DMD:p.K1772N, DPEP1:p.V11L, ERBB2:p.S310F,         ERBB2:p.D769Y, ERBB3:p.E928G, ESYT1:p.R816W, FAM179A:p.A831T,         FAM58BP:p.A70T, FMN2:p.S751F, GALNTL6:p.K567del, GATA3:p.L328fs,         GATA3:p.N334fs, GATA3:p.L344fs, GATA3:p.H400fs, GATA3:p.S408fs,         GATA3:p.S430fs, GATA3:p.H434fs, GATA3:p.H435fs, GDAP1:p.T307A,         GRB14:p.A300T, GUCY2C:p.G549C, IL17B:p.R34W, KCNB2:p.R231H,         KIF1B:p.R1320W, KIF26B:p.V1113M, KLF4:p.K434Q, LY9:p.I69L,         MAP2K4:p.S184L, MAP2K4:p.S251L MAP2K4:p.T261fs, MAP3K1:p.L318fs,         MAP3K1:p.I761fs, MAP3K1:p.V1346del, MAP3K1:p.L1384fs,         MAPK13:p.E315K, MAPK4:p.V100M, MARCH5:p.R170C, MBP:p.E120K,         MEFV:p.R377H, METTL15:p.Q53E, MS4A4A:p.V99M, MUC17:p.R4415H,         MYH6:p.T847M, MYO5B:p.A405V, NARS2:p.P240R, NLGN4X:p.D382N,         NLRC4:p.R288W, OR13G1:p.R258H, OR2AK2:p.V451, OTOF:p.T388M,         PACSIN2:p.Q331H, PALM2-AKAP2:p.A299T, PCDH19:p.R286C,         PCDHGC5:p.D664N, PIK3CA:p.R88Q, PIK3CA:p.E110del,         PIK3CA:p.K111del, PIK3CA:p.PVPHGLEDL447del, PIK3CA:p.L455fs,         PIK3CA:p.M1004I, PIK3CA:p.M1043I, PIK3CA:p.N1044Y,         PIK3R1:p.KPDL567del, PREX2:p.R363Q, PRRX1:p.A196V,         PTEN:p.V317fs, RGSL1:p.V222I, RUNX1:p.R142fs, RUNX1:p.D96fs,         SCN2A:p.R36K, SLC25A32:p.Q83E, SLC25A45:p.G106C, STRA6:p.Q68R,         STX6:p.H153D, TBX3:p.H187Y, TFPT:p.S252C, TINAG:p.R332W,         TMEM71:p.R63Q, TP53:p.E286K, TP53:p.R282W, TP53:p.V272M,         TP53:p.S241fs, TP53:p.C238fs, TP53:p.C238F, TP53:p.C238Y,         TP53:p.Y234C, TP53:p.Y220S, TP53:p.R209fs, TP53:p.G199V,         TP53:p.L194R, TP53:p.H193L, TP53:p.H193Y, TP53:p.V173L,         TP53:p.V173M, TP53:p.K132N, TP53:p.R110fs, TUBD1:p.A200V,         VLDLR:p.R231H, VWA3A:p.V955I, VWF:p.K1720N, XPO1:p.E571K, and         ZNF268:p.F901 del.

48. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from COAD; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         KRAS:p.G12D, BRAF:p.V600E, KRAS:p.G12V, ACVR2A:p.K435fs,         GRB14:p.KKK295del, SEC63:p.L532fs, TGFBR2:p.E125fs,         ATR:p.K771fs, ICA1:p.N204fs, KRAS:p.G12C, TP53:p.R175H,         ABCA8:p.R842Q, ACTL7B:p.R354H, ACVR2A:p.K435fs, AIM2:p.K340fs,         ALG2:p.S302Y, ANKIB1:p.K144fs, ARSG:p.V131I, ATP10D:p.R311H,         AXIN2:p.W663fs, C5orf30:p.D4N, CACNG3:p.V134I, CASP5:p.K78fs,         CC2D2A:p.R1284C, CDH10:p.E349K, DNMT1:p.E432K, DOCK2:p.G170R,         DOCK5:p.E177K, EGR2:p.R390H, ERBB3:p.V104M, FAM135B:p.R884H,         FBXW7:p.R505C, FBXW7:p.R465H, FHDC1:p.R254W, FOXL1:p.N89K,         HCN4:p.R525H, HLA-DMA:p.E84K, HTR3B:p.R236C, ITGA4:p.T673M,         KIF18A:p.R17C, KIF20B:p.E991K, KLHL5:p.R326C, KRAS:p.A146T,         KRAS:p.G13D, LPHN3:p.R1183Q, MAP2K4:p.R287H, MAPK8IP1:p.L217fs,         MFSD5:p.R280Q, MUC16:p.R8606H, MYO6:p.D1180N, NAA25:p.S807Y,         NBPF14:p.V44L, NRAS:p.Q61K, NRAS:p.G13R, PAX3:p.T424M,         PGAM1:p.R240H, PHF3:p.R1410I, PIK3CA:p.R88Q, PIK3CA:p.E545K,         PIK3CA:p.H1047R, PLXNA3:p.V14fs, POSTN:p.R508C, PTPRU:p.D1434N,         PYGO2:p.Q150fs, RBBP7:p.E274K, SFPQ:p.R611Q, SGSM1:p.F117L,         SLC25A40:p.R96Q, SLC8A1:p.R431H, SLITRK3:p.S298L,         SPATA22:p.S150L, SUN3:p.E128K, TGFBR1:p.S241L, TP53:p.R273H,         TP53:p.R273C, TP53:p.R248W, TRPV5:p.R492H, USP40:p.S851L,         VPS13C:p.D1359Y, ZBTB24:p.L607I, ZNF434:p.R306C, ZNF443:p.R301I,         ZNF484:p.R138C, and ZNF770:p.S441P.

49. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from GBM; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         HSD17B7P2:p.N175S, IDH1:p.R132H, EGFR:p.A289V, EGFR:p.G598V,         WASH3P:p.G175S, ZNF814:p.D404E, RPSA:p.Q111E, NBPF10:p.E3455K,         TP53:p.R248Q, BRAF:p.V600E, EGFR:p.A289T, PRB2:p.N230del,         RGPD5:p.P1760A, TP53:p.R175H, CHEK2:p.K373E, EGFR:p.R108K,         EGFR:p.R222C, PIK3CA:p.E545K, PIK3R1:p.G376R, POTEC:p.K507E,         SDHAP2:p.V195E, SLC6A10P:p.K88N, TP53:p.R282W, TP53:p.R273H,         CD3EAP:p.K219del, DST:p.R146C, EGFR:p.A289D, EGFR:p.H304Y,         FRG1B:p.S71N, GOLGA8DP:p.A116E, KRTAP4-11:p.R121K,         KRTAP4-11:p.S48R, MAP3K1:p.P324L, OGDH:p.I78fs, PODXL:p.S162fs,         PSPH:p.V145I, SPINT1:p.A316V, TP53:p.R248W, TP53:p.G245S,         TP53:p.Y220C, TP53:p.R158H, TSHZ2:p.A222T, UBC:p.L149R,         ZDHHC4:p.R300H, ZNF844:p.R447P, AASS:p.T878fs, ABCC10:p.R570W,         ADAM29:p.V205I, ADAMTS8:p.V524M, AGAP3:p.R766W, AICDA:p.Y144F,         AK7:p.A159V, AK8:p.D243A, ANO2:p.R334C, AOX1:p.A507V,         ARHGAP5:p.M691L, CALN1:p.V2311I, CARM1:p.A202V, CD163L1:p.V721M,         CD1D:p.L25fs, CD209:p.A283T, CDH18:p.A195T, CILP2:p.V553M,         CIZ1:p.L89P, CLOCK:p.L123fs, COL6A5:p.T2224M, CSF2RB:p.G298S,         CSMD3:p.E171K, CYP2D6:p.H352R, DCAF12L1:p.R335H,         DCAF12L2:p.R246H, DPP10:p.V183I, DPY19L2P1:p.R378Q,         DQX1:p.R505H, DRD5:p.S275R, DVL2:p.V66G, EFCAB6:p.R379K,         EGFR:p.L62R, EGFR:p.R252C, EGFR:p.P596S, EGFR:p.P596L,         EGFR:p.G598A, EGFR:p.E709K, EPHA1:p.A184T, ERC2:p.R20H,         ESPNP:p.R627Q, FAM126B:p.R382H, FBN3:p.V886I, FGF14:p.T229M,         FLG2:p.H1901fs, FLG:p.R2886H, FLNA:p.V1240M, FOXG1:p.H57del,         FPR2:p.R54Q, FRG1B:p.K13N, FRG1B:p.A53T, GABRA6:p.V314L,         GJB3:p.R160H, GLT8D2:p.A178V, GRM3:p.R183C, HERC1:p.R2330H,         HNF1B:p.T417M, HTRA3:p.Q403R, IDH1:p.R132G, IFNA10:p.L80F,         IFNA10:p.V79A, JHDM1D:p.R313H, JPH1:p.A395T, KEL:p.V411M,         KIAA0907:p.R516fs, KIAA1704:p.D88del, KLK6:p.R120H, KRAS:p.G12D,         KRTAP4-7:p.L121V, KRTAP4-7:p.L148V, KRTAP5-4:p.S131C,         LAT2:p.L18W, LIMK2:p.R203H, LUM:p.R330C, MCOLN3:p.V141I,         MGAT4B:p.T444P, MUC17:p.V77M, MUC17:p.3204_3205insP,         MYO1D:p.T109M, MYO6:p.Q914fs, NAP1L5:p.140_141EE>E,         NF1:p.F1658fs, NHP2L1:p.R84C, NLRP5:p.R737W, NPTX1:p.A263T,         NUFIP2:p.Q29del, ODF4:p.R61C, OR11H12:p.H154P, OR2A7:p.V18I,         OR2H1:p.V287I, OR2T12:p.R184H, OR5D13:p.R236C, OR5P2:p.A100V,         OR6N2:p.R293C, PASD1:p.A236del, PCDH11X:p.T486M,         PCDHB13:p.P221L, PDGFRA:p.E229K, PDGFRB:p.S650L, PHC3:p.T35del,         PIK3C2B:p.R287fs, PIK3CA:p.M V, PIK3CA:p.R88Q, PIK3CA:p.M1043V,         PIK3CA:p.H1047R, PIK3R1:p.K379N, PODNL1:p.A150V, POTEE:p.V166M,         POTEG:p.R136H, PRKCD:p.G432fs, PROKR2:p.V297I, PTEN:p.C136Y,         PTEN:p.S170N, PTEN:p.R173H, PTEN:p.T277I, PTEN:p.V317fs,         PTPN14:p.E716del, R3HDM2:p.412_413QQ>Q, RAB11FIP5:p.R170H,         RASAL3:p.R82H, RB1:p.N316fs, RDH8:p.A198V, REN:p.15_16LL>L,         RIMBP2:p.R830H, SCAF11:p.E926fs, SCN7A:p.R1358H, SCNN1G:p.R564H,         SDHAP2:p.R31C, SDHAP3:p.A66T, SEMG2:p.R292C, SH3RF2:p.R318C,         SHB:p.A460T, SIGLEC10:p.T250M, SLC13A5:p.Q273P, SLC17A9:p.V324I,         SLC22A9:p.R407Q, SLC26A3:p.V881, SLC5A3:p.A302fs,         SLC9A4:p.R631H, SPAM1:p.R346Q, SPEN:p.E803fs, SPTA1:p.A2011V,         SUSD5:p.T513M, SYNE1:p.R8468H, TARSL2:p.G366D, TAS2R41:p.A255T,         TAT:p.R367H, TFPI2:p.R206C, THSD7B:p.R90C, TMEM147:p.A92V,         TMEM156:p.R81C, TMPRSS6:p.V302L, TNFSF9:p.A232T, TP53:p.C238F,         TP53:p.C238Y, TP53:p.Y234C, TP53:p.V216M, TP53:p.H179R,         TP53:p.T155N, TRAPPC10:p.K133fs, TTN:p.R21402W, TTN:p.V16403M,         TUBBP5:p.V102M, TYRP1:p.T352fs, UBC:p.R73L, UGT2B28:p.P289H,         USH2A:p.R3719H, WASH6P:p.L211V, ZFP42:p.V227I, ZFP42:p.T264M,         ZNF181:p.V305G, ZNF280B:p.E400K, ZNF534:p.N583K,         ZNF563:p.W208fs, ZNF844:p.F487L, and ZPBP:p.R154C.

50. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from HNSC; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         PIK3CA:p.E545K, PIK3CA:p.E542K, TP53:p.R175H, PIK3CA:p.H1047R,         TP53:p.R282W, TP53:p.R248Q, TP53:p.R273H, TP53:p.R248W,         TP53:p.G245S, RHOA:p.E40Q, EP300:p.D1399N, HRAS:p.G13V,         MB21D2:p.Q311E, NFE2L2:p.E79Q, TP53:p.H179Y, FBXW7:p.R505G,         HIST1H2BF:p.E77K, HRAS:p.G12D, MAPK1:p.E322K, NFE2L2:p.D29H,         TP53:p.P278S, TP53:p.C242F, TP53:p.Y220C, TP53:p.H193L,         TP53:p.H179R, TP53:p.V157F, TP53:p.R110L, AKNAD1:p.K620R,         ANXA6:p.R231Q, AP1G2:p.D243N, ATAD5:p.D441N, ATP6AP2:p.E119Q,         B2M:p.M1I, BCL11A:p.E579K, C1orf172:p.Y30fs, C7orf57:p.E30K,         CCDC135:p.E313K, CDH12:p.P706T, CDH7:p.Q225K, CDK11B:p.E79del,         CDKN2A:p.H83Y, CHCHD4:p.T79M, CIRH1A:p.S250I, CLSTN2:p.P759L,         CRB1:p.L628fs, DENND5B:p.G1023E, DNAH5:p.Q1797E, DSP:p.R160G,         EDA:p.L58F, EFCAB6:p.E1002K, ELF4:p.S415L, EP300:p.C1164Y,         EPHA3:p.T802R, EPHA6:p.D952H, ERBB2:p.M916I, ESRRA:p.D219N,         FAM101A:p.I89del, FBXO24:p.M553V, FCAR:p.V233M, GPANK1:p.Y351fs,         GPR20:p.V300I, GPRASP1:p.S706L, GPRIN3:p.R633fs, GRID2:p.T649fs,         GRM3:p.F682L, GUCY2F:p.S404L, HCRTR2:p.D100Y, HIST1H3C:p.K37M,         HIST1H4C:p.R68P, HLX:p.S12T, HOXD10:p.Y151C, HPS3:p.K812N,         HRAS:p.G12A, HRAS:p.G12S, IFT140:p.E664K, INPPL1:p.T493M,         ITGA10:p.R669Q, ITGB1:p.D158N, KIAA1429:p.D1526N,         KIAA1429:p.S138F, KPRP:p.E553fs, KSR2:p.T555M, LINGO2:p.P410T,         LPCAT1:p.V187del, MAGEB3:p.V75A, MAP3K7:p.E524Q,         MAP4K3:p.P657fs, MAP9:p.K485N, MARS2:p.R481Q, MBOAT7:p.R424W,         MUC16:p.R12774H, MUC5B:p.T4388M, MYH11:p.E993K, MYOCD:p.T493M,         MYOM1:p.R63Q, NANOS3:p.S183L, NCOR1:p.R1561Q, NCOR1:p.Q169E,         NCR1:p.D213N, NFE2L2:p.E79K, ODZ1:p.R366M, OPN1MW:p.A285T,         OR2M2:p.A95fs, OR2M3:p.M273I, OR2T33:p.R120S, OR6V1:p.1248fs,         PABPC5:p.P58L, PACSIN1:p.E359K, PIK3CA:p.M1043V,         PIK3CA:p.H1047L, PIWIL1:p.V699M, PLIN5:p.430_431insNG,         PLXNA3:p.P58S, PRB1:p.R274fs, PRSS1:p.D107N, RAC1:p.A159V,         RGS7:p.L21fs, RPA1:p.R31H, RPL18:p.R178fs, SF11:p.R821Q,         SLC35D3:p.*417S, SLC5A7:p.G336C, SMARCA4:p.P913L, STAT3:p.D661V,         SYCP2:p.K474N, SYT6:p.R249H, TBX21:p.E494K, THSD7A:p.R1046C,         THSD7A:p.C728F, TMC3:p.R934S, TMTC2:p.T409R, TP53:p.E285K,         TP53:p.C275F, TP53:p.R273C, TP53:p.G266E, TP53:p.G262V,         TP53:p.R249S, TP53:p.G245V, TP53:p.C238F, TP53:p.M237I,         TP53:p.Y236C, TP53:p.Y236D, TP53:p.R196P, TP53:p.PHHERC177del,         TP53:p.V173L, TP53:p.V173M, TP53:p.Y163C, TP53:p.P151T,         TP53:p.V143M, TP53:p.P58fs, URI1:p.S13fs, ZNF177:p.K384N,         ZNF750:p.S96fs, and ZZZ3:p.R5Q.

51. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from KIRC; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         WASH3P:p.G175S, VHL:p.L89H, VHL:p.S111N, WDR52:p.V1227G,         KRT1:p.552_559YGSGGSSY>Y, KRTAP1-1:p.S34C,         PALM2-AKAP2:p.1075_1076insEA, ZNF814:p.D404E, DOPEY2:p.Y2048S,         KAT2B:p.W111fs, PABPC1:p.E156fs, PCDHGC5:p.G599V,         PIK3CA:p.E545K, RRAD:p.A278E, SIRPA:p.D131del, UQCRFS1:p.I83V,         VHL:p.P45L, VHL:p.V74D, VHL:p.R82P, VHL:p.L116fs, VHL:p.L158V,         VHL:p.L169P, WDR73:p.DGTRSQ315del, ABCA3:p.E95D,         ABCC5:p.L1090fs, ACADS:p.R330H, ACAN:p.G952E, ACSM2A:p.L402fs,         ADAM23:p.K380M, ADH1A:p.D154V, AFF3:p.SA620del, AGAP6:p.D69fs,         AGAP7:p.E71fs, AHNAK:p.5_6insE, AIDA:p.K247M, ALAS1:p.G302R,         ANAPC16:p.R95fs, ANK2:p.N453S, ANKRD36:p.K378R, ARHGEF5:p.E487G,         ARSD:p.AGV234del, ARSD:p.A234G, ATP2A1:p.G704C, ATP7A:p.Q990fs,         AVIL:p.G299fs, AXDND1:p.EQ991del, BAP1:p.N78S, BAP1:p.M1I,         BLM:p.H660Q, BMPER:p.RIAL444del, BRK1:p.K70Q, BTRC:p.I416M,         C16orf55:p.D118A, C19orf33:p.K102E, C20orf132:p.E382D,         C2orf71:p.1225_1226insS, C6orf132:p.173_182PPPLLLEPPP>P,         CASP5:p.R23fs, CATSPER4:p.T425M, CCDC120:p.I8V, CCR5:p.S185I,         CCZ1:p.E214D, CD7:p.P174fs, CDAN1:p.L646fs, CDH23:p.F1132Y,         CDK5RAP2:p.H1592Q, CENPB:p.E410V, CERCAM:p.A85fs, CHEK2:p.K373E,         CHIT1:p.P284fs, CLCN2:p.645_645R>RR, CLUL1:p.G463R,         CNTNAP4:p.Y436S, CUL9:p.D1726E, CWC25:p.K364E, CXorf51B:p.V431,         DDX39B:p.F149fs, DIRAS1:p.G79C, DISP2:p.F1021S, DNMBP:p.T78P,         DOCK8:p.A177fs, DPCR1:p.H383N, DPCR1:p.L768del, EGFR:p.L838M,         ENPEP:p.F289C, ESPNP:p.W122fs, FAM105A:p.H126N,         FAM186A:p.IPPQAQELEIPL1556del, FAM194B:p.EEEEYL135del,         FAM22F:p.S691 del, FAM22F:p.P690fs, FAM47A:p.LRPEPPETGVSH235del,         FAM47C:p.P388S, FAM78A:p.W192L, FBXO34:p.Q294fs, FGFR3:p.R571fs,         FGFR3:p.P716H, FMN2:p.AIPPPPPLPGA956del, FOXD4L4:p.C405fs,         FUT6:p.S140fs, GJA1:p.A31 fs, GOLGA5:p.L492I, GPM6A:p.A50V,         GPRIN1:p.231_239RKEDPGSLR>R, GRAMD1B:p.P356H, GREB1:p.S344Y,         GRM6:p.A718fs, GUSB:p.L501V, GUSB:p.C500R, HBB:p.F86C,         HDAC6:p.G977D, HEXDC:p.T482P, HNFJB:p.N302K, HNRPLL:p.M327V,         HRC:p.P439fs, HSFX2:p.D92E, IL1RAP:p.F50C,         IVL:p.EQQEGQLKHP167del, KANK4:p.S253P, KCNJ18:p.E378K,         KIAA1751:p.K97N, KRT1:p.SSYGSGG557del, KRT2:p.L299W,         KRT4:p.F154fs, KRTAP10-6:p.49_49P>PSCCAP, KRTAP5-7:p.C120Y,         KRTAP9-2:p.CCQP140del, LARS:p.P185fs, LCP1:p.P445fs,         LOC338651:p.PHRSHSPPWS102del, LRCH2:p.D717G, LTA4H:p.F107L,         LYST:p.Q710H, MAFA:p.207_208HH>H, MAGEC1:p.P239del,         MAP2K5:p.Q445R, MAPKAPK2:p.T214fs, MARCKS:p.K152fs,         MED12L:p.P2071 S, MEGF6:p.A582fs, MGST3:p.G143fs,         MLXIPL:p.S790R, MOCOS:p.S849P, MST1R:p.M464V, MTOR:p.C1483F,         MTOR:p.L1460P, MUC16:p.P11260A, MUC17:p.R1227fs,         MUC17:p.H1228fs, MUC2:p.1480_1481insI, MUC6:p.P1569fs,         MYO3A:p.N525S, NBPF3:p.D491V, NCOR1P1:p.L52P, NDUFA4L2:p.G3fs,         NEFH:p.651_651K>KAKSPEK, NES:p.V611L, NFAT5:p.Q906E,         NOXO1:p.G3fs, NR2C1:p.S270I, NSMCE2:p.Q31fs, NUDT21:p.W13fs,         ODZ2:p.W628fs, ONECUT1:p.L424M, OR10A3:p.F73V, OR4F4:p.E15G,         OR4N2:p.L150fs, OR51B5:p.A66fs, OR7C1:p.F104fs, PABPC1:p.Y408F,         PABPC1:p.K333fs, PABPC1:p.A181T, PABPC3:p.P191T, PALLD:p.A996T,         PALM2-AKAP2:p.G1118fs, PARD6A:p.G84fs, PASK:p.T62I,         PCDH15:p.C1713F, PCNT:p.G136S, PGM5:p.G426fs, PGPEP1L:p.R164fs,         PIK3C2B:p.F1473L, PIK3CA:p.N1044K, PIK3R5:p.L371R,         PITRM1:p.P816T, PLIN4:p.T347I, PODXL:p.28_30PSP>P,         POLR1C:p.K332Q, POTED:p.I214V, PPM1E:p.R311W, PRKCE:p.Q157fs,         PROX1:p.V225D, PRRC2C:p.P1883T, PRX:p.P549L, PSD3:p.T563P,         PTCH1:p.P689H, RANBP3:p.L386W, RASGEF1C:p.A188T, RGPD6:p.F946L,         RHEB:p.Y35N, RIMBP3:p.A396del, RIN3:p.L449V, RLIM:p.S501L,         RNF17:p.S351C, RUNX2:p.P466H, SCAF1:p.P208fs, SDK1:p.K508fs,         SECISBP2:p.D608E, SERPIN B3:p.S209C, SESTD1:p.I306M,         SFRP4:p.P325fs, SH3KBP1:p.P563fs, SIPA1L3:p.G777A,         SLC13A2:p.L493fs, SLC16A9:p.CVLLGG470del, SLC25A5:p.A118T,         SLC44A5:p.V70F, SLC4A8:p.N229K, SLC52A1:p.G370del,         SLC52A2:p.G399fs, SLC6A10P:p.K88N, SLC6A4:p.A85fs,         SLC9B1:p.V446fs, SON:p.VLESSAVT1359del, SP8:p.G165del,         SPAG1:p.353_354insD, SPATA9:p.C189F, SPEG:p.A992fs,         SPTB:p.T1864I, SRA1:p.V110L, STAT6:p.P354fs, STK11IP:p.A155E,         STXBP3:p.E279G, SVIL:p.M93T, SYNE1:p.R8468S, SYNJ2:p.K832T,         SYNPO:p.G619fs, TAOK2:p.Q899fs, TAS2R38:p.1311T,         TBC1D12:p.F608Y, TBC1D1:p.H277R, TBC1D3:p.A556fs,         TBC1D3C:p.A495fs, TBC1D3F:p.A556fs, TCF7:p.H140P,         TDRD10:p.W276C, THRAP3:p.K551R, TMEM102:p.A110P,         TMEM161B:p.L142P, TMEM230:p.D140G, TMEM47:p.G87S, TRDN:p.*730Y,         TTBK1:p.T1065S, UBE2O:p.R1118fs, UBR5:p.T1306fs, UPK3A:p.G272fs,         VHL:p.G39S, VHL:p.S65L, VHL:p.N78D, VHL:p.R79P, VHL:p.W88L,         VHL:p.L89P, VHL:p.R107P, VHL:p.S111R, VHL:p.H115N, VHL:p.D121Y,         VHL:p.G123fs, VHL:p.D126fs, VHL:p.L128H, VHL:p.L135F,         VHL:p.I151T, VHL:p.L153P, VHL:p.L158P, VHL:p.Q164fs,         VHL:p.L184P, VHL:p.L188P, WASH6P:p.315_316insAPP,         WASH6P:p.T201M, WWP2:p.G458A, ZCCHC6:p.K937N, ZFAND2B:p.I49T,         ZFR2:p.Y107N, ZNF273:p.N319K, ZNF462:p.S650T, ZNF516:p.A256D,         ZNF519:p.H431Y, ZNF687:p.F858C, ZNF732:p.E227Q, ZNF880:p.Q406R,         ZP3:p.V362fs, and ZRANB1:p.*735fs.

52. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from LAML; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         NPM1:p.W288fs, DNMT3A:p.R882H, NPM1:p.L287fs, IDH2:p.R140Q,         IDH1:p.R132C, FLT3:p.D835Y, DNMT3A:p.R882C,         FLT3:p.600_601insFREYEYD, IDH1:p.R132H, NRAS:p.G13D,         U2AF1:p.S34F, KIT:p.D816V, FLT3:p.D835E, IDH2:p.R72K,         NRAS:p.G12D, WT1:p.S381fs, ABTB1:p.L249fs, DNMT3A:p.R736H,         FLT3:p.D835H, KRAS:p.G12D, NPM:p.L287fs, NRAS:p.Q61H,         NRAS:p.Q61K, PHACTR1:p.V251fs, RBBP4:p.E330K, RUNX1:p.R135G, and         U2AF1:p.S34Y.

53. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from LUAD; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         KRAS:p.G12C, KRAS:p.G12V, EGFR:p.L858R, U2AF1:p.S34F,         KRAS:p.G12A, TP53:p.R158L, KRAS:p.G12D, PIK3CA:p.E545K,         TP53:p.R273L, EGFR:p.ELREA746del, KRAS:p.G13D, A2ML1:p.S654fs,         BRAF:p.G469V, CTNNB1:p.S37F, EGFR:p.G719A, KRAS:p.G13C,         MYOF:p.G165fs, EGFR:p.S768I, FAM47C:p.G948W, KRAS:p.Q61L,         MYH10:p.L1091fs, NRAS:p.Q61L, OR4C3:p.H130fs, PI15:p.V22F,         RAD50:p.D69Y, RIT1:p.M90I, TP53:p.C275F, TP53:p.R249M,         TP53:p.R249G, TP53:p.R248P, TP53:p.R175H, TP53:p.Y163C,         TP53:p.A159P, TP53:p.V157F, TP53:p.G154V, ABCB1:p.R467L,         ACBD3:p.R224L, ACTA1:p.G275C, ACTN2:p.D893Y, ADAM30:p.Q741H,         ADAMTS14:p.G238C, ADAMTS20:p.R1251S, ADAMTS20:p.R541L,         ADAMTS5:p.L549M, ADAMTS9:p.G659W, ADCY2:p.P1016T, ADCY5:p.G623C,         AFP:p.A182G, AHDC1:p.P155Q, AKAP1:p.LDRNEEG317del,         ALKBH1:p.K137E, ANK2:p.Q3076L, ANKRD44:p.G339C, ANO3:p.A41S,         AP1G1:p.R723L, APBB2:p.T243fs, APOB:p.L973M, APOBR:p.R840L,         AQP10:p.Q261L, ARAP3:p.R1226L, ARFIP2:p.R86L, ARHGAP36:p.P16H,         ARL13B:p.R358L, ASCC2:p.R365L, ASPM:p.S240F, ASXL3:p.P1470Q,         ATRN:p.P197Q, AVIL:p.G64W, AXDND1:p.W101R, B3GAT1:p.R125L,         BARX2:p.R68P, BCL9L:p.G980C, BCOR:p.N1459S, BEND2:p.P536Q,         BMS1:p.G455V, BRAF:p.V600E, BRAF:p.G466V, BRD9:p.G330W,         BRF1:p.V469L, BRWD3:p.H160N, BTRC:p.G260W, C11orf68:p.V135L,         C15orf2:p.V753F, C15orf2:p.G906W, C18orf8:p.M61I,         C1GALT1:p.G299V, C1orf173:p.G1454S, C1orf173:p.S688Y,         C1orf87:p.R541L, C2orf53:p.P272H, C3orf20:p.R740L, C7:p.R687S,         C7orf58:p.G140W, C7orf58:p.R238L, CACNA1A:p.S772Y,         CACNA1D:p.R1073L, CACNA1E:p.R2089Q, CACNA2D1:p.A352E,         CACNG3:p.R232W, CADPS:p.R959S, CALB2:p.R258C, CAMK2B:p.G131V,         CARD11:p.I1065M, CCDC111:p.R417L, CCDC141:p.E1204V,         CCDC19:p.R279L, CCDC19:p.R207L, CCKAR:p.L271M, CD1B:p.W41L,         CDH10:p.S577R, CDH10:p.R472C, CDH10:p.R128S, CDH18:p.A721S,         CDH20:p.P433H, CDH6:p.Q237K, CDK13:p.R880S, CDK4:p.R24L,         CELF4:p.A309P, CFDP1:p.P129fs, CHN1:p.K264N, CHRNA4:p.S396R,         CHRNA9:p.P361Q, CLCNKA:p.P124Q, CLEC12B:p.W217L, CLK4:p.R68L,         CNTFR:p.D252Y, CNTN6:p.R807M, CNTNAP2:p.F395L, COL19A1:p.P538Q,         COL5A2:p.G612W, COL5A2:p.G516W, COL9A1:p.P211Q, CPE:p.P290Q,         CPNE8:p.Q127H, CPSF4:p.P219Q, CRIPAK:p.S180fs, CROT:p.Q580H,         CRTC3:p.S363L, CSMD2:p.P1855Q, CSMD3:p.T2810N, CSMD3:p.P2727T,         CSMD3:p.Q174H, CUBN:p.G596C, CUL4B:p.R91S, CUL7:p.L371F,         CXCL9:p.K122N, CXCR4:p.E345Q, CXorf59:p.R198M, CYP11B1:p.R498G,         CYP27A1:p.P112Q, CYP2B6:p.A444E, DACH2:p.R539L, DCC:p.R446H,         DDX56:p.R329L, DEFA1:p.W90C, DENND2A:p.R688Q, DENND2A:p.R499L,         DMBT1:p.R1521L, DNAH5:p.R3822L, DNAH9:p.S2993R, DNAI2:p.V231L,         DPP6:p.L757F, DSG4:p.R128L, DST:p.A4410S, DZIP3:p.M322L,         EBF3:p.R231 S, EFCAB4B:p.E265Q, EHHADH:p.Q704H, ELAVL2:p.L263F,         EMR1:p.R493H, ENAH:p.R514L, ENPP1:p.G738E, EPB41L3:p.A896S,         EPG5:p.R2289L, EPHA1:p.G111V, EPHB6:p.R337H, EPRS:p.V1151L,         ERBB2:p.S310Y, ERBB2:p.774_775insAYVM, ERBB2:p.776_776G>VC,         ERN2:p.T295K, FAM120B:p.P467H, FAM127C:p.F52L, FAM135B:p.W240C,         FAM210B:p.L112F, FAM47A:p.R690L, FAM47B:p.W163C, FAM47B:p.L567F,         FAM5C:p.R457G, FAM70B:p.P277T, FAM71B:p.L583M, FAM75A6:p.R304S,         FAM75A6:p.P54L, FAM75D1:p.R1265S, FARP1:p.R299L, FAT1:p.R4359L,         FAT3:p.R1266H, FAT3:p.G1899V, FAT3:p.H3574N, FBXO18:p.M144I,         FBXO31:p.G443fs, FCGBP:p.A1022S, FCRL2:p.V505L, FERD3L:p.P92H,         FGB:p.E339Q, FGFR2:p.E116K, FGFRL1:p.R243L, FGFRL1:p.V274L,         FKBPL:p.R320L, FLG2:p.G1545V, FLG2:p.L572F, FLG:p.P3254H,         FLG:p.P2466Q, FMN2:p.P992T, FOLH1:p.A643S, FOXRED1:p.R136L,         FRAS1:p.C382F, FRG2B:p.D142Y, FRMPD1:p.E1093Q, FSHB:p.T43N,         GABRA5:p.Q224K, GADL1:p.L352I, GAL3ST3:p.A271S, GALNT14:p.D234E,         GAS8:p.R313S, GATA3:p.M443I, GCDH:p.R82C, GEM:p.R268L,         GFRAL:p.Q308K, GIT2:p.R123L, GJB4:p.R22S, GLB1L2:p.I407M,         GLOD4:p.Q223fs, GNAO1:p.P283Q, GPNMB:p.174M, GPR137B:p.G240C,         GPR158:p.P762T, GPR98:p.G4307W, GRB7:p.R239L, GRHL1:p.G608W,         GRID1:p.R683L, GRIK1:p.R368Q, GRM5:p.P895fs, GTF2E1:p.R192L,         H3F3C:p.R131L, HAO2:p.H12N, HCN1:p.P231Q, HECW1:p.A183S,         HGF:p.M686T, HIP1:p.R940L, HIST1H1E:p.R25P, HLA-DMA:p.A236fs,         HOXA5:p.G11C, HS3ST3A1:p.G399W, HSD17B6:p.F209L, HSPA13:p.V85L,         HSPBAP1:p.R282L, HTR5A:p.W298C, IGHMBP2:p.R615S, IL2:p.R103M,         IL2RA:p.G61W, IL32:p.P215T, ING1:p.A220S, INMT:p.G56V,         ITGA8:p.G616C, ITGAD:p.L528fs, ITGAX:p.R283H, ITIH1:p.G254W,         ITIH2:p.L842V, ITK:p.R29L, ITPR2:p.P358Q, JMJD1C:p.R1198S,         KCNA1:p.G376C, KCNH8:p.M455I, KCNJ3:p.L430F, KCNK18:p.G23V,         KCNK2:p.R166L, KEAP1:p.G603W, KEAP1:p.R260L, KEAP1:p.S144F,         KHDRBS2:p.S203L, KIAA1211:p.P1203Q, KIAA1549:p.L1272F,         KIAA1755:p.Q108H, KIF15:p.E252Q, KIF9:p.G480R, KIRREL:p.G604C,         KLF5:p.E419Q, KRAS:p.Q61H, KRTAP10-12:p.R64P, KRTAP27-1:p.M124I,         KRTAP4-5:p.C91F, KRTAP5-1:p.S193Y, L1CAM:p.R632S,         L3MBTL4:p.W162L, LAMA1:p.D1030Y, LAMB1:p.T1610fs,         LAMB4:p.G1239W, LAMB4:p.G588W, LEF1:p.I53V, LEKR1:p.Q450K,         LIM2:p.S150T, LIPJ:p.P236Q, LPHN3:p.E740D, LPPR4:p.R527S,         LRFN5:p.N132K, LRP1B:p.G3563C, LRP2:p.M4039I, LRRC4C:p.Q1L,         LRRIQ1:p.W792L, LRRTM4:p.S243Y, MAGEA10:p.R7H, MAGEC2:p.W109C,         MAGI1:p.G1156V, MAGI2:p.P1044T, MAK:p.P373Q, MAP2K1:p.K57N,         MARCH11:p.R193L, MEPE:p.G142C, MKI67:p.R1081 S, MKRN3:p.P448H,         MLL3:p.N393K, MLL3:p.Q356K, MMRN1:p.A1013S, MOGAT2:p.Q66fs,         MXRA5:p.D324Y, MYH4:p.T790M, MYH8:p.R1117C, MYH8:p.H1006N,         MYO5B:p.R708L, MYO7B:p.P2040H, MYO9B:p.R94L, MYT1L:p.P351Q,         NAA11:p.T184K, NAB1:p.L72F, NAV1:p.R938L, NBPF15:p.G665E,         NCAM2:p.G698C, NCAPD2:p.R220L, NDST3:p.V427I, NEK2:p.R239S,         NFIA:p.L294F, NLRP3:p.R157C, NOTCH2:p.R2105L, NR4A2:p.R314L,         NRG1:p.V481L, NRXN1:p.R813S, NRXN1:p.A660S, NRXN3:p.P23H,         NRXN3:p.R103C, NTM:p.G333C, NUAK1:p.G173C, NYAP2:p.P437L,         ODZ3:p.P218Q, OIT3:p.R508S, OOEP:p.R101C, OPN1LW:p.P283H,         OR10H4:p.M199I, OR10J1:p.L157Q, OR10X1:p.L298I, OR10Z1:p.L205F,         OR14A16:p.G160C, OR2A25:p.M80L OR2AG2:p.G249W, OR2AK2:p.W37C,         OR2H2:p.L205F, OR2J2:p.G234W, OR2L13:p.M106I, OR2L13:p.T242A,         OR2L3:p.M1I, OR2L3:p.L67I, OR2L8:p.R121C, OR2L8:p.R171S,         OR2M2:p.F177L, OR2M2:p.F323L, OR2M5:p.V205L, OR2T12:p.M258L,         OR2T27:p.D1 Y, OR2T33:p.P165Q, OR2T34:p.C246F, OR2T6:p.V213L,         OR4C12:p.D309Y, OR4C12:p.M279I, OR4C16:p.L162M, OR4M2:p.A119S,         OR4M2:p.A161 S, OR51V1:p.P298T, OR5AS1:p.M391, OR5B12:p.S289C,         OR5B17:p.M266I, OR5D14:p.H246N, OR5D16:p.P264T, OR5D18:p.R123H,         OR5F1:p.G44V, OR5J2:p.A36S, OR5L1:p.T275N, OR6C65:p.I154fs,         OR6C75:p.G94W, OR6K2:p.P79Q, OR8D2:p.R306M, OR9A2:p.R289W,         OR9G9:p.R169L, P2RX7:p.P142Q, P2RY10:p.T10K, P2RY10:p.V196L,         PABPC5:p.R99S, PAPPA2:p.P917T, PAPPA2:p.P1706H, PBLD:p.P55Q,         PCDH10:p.R587S, PCDH10:p.V986L, PCDH11X:p.R1010I,         PCDHAC2:p.A742V, PCDHB5:p.P649S, PCDHGC5:p.K12N,         PCDHGC5:p.P684H, PCLO:p.P3946T, PCMTD1:p.R271M, PDPR:p.G793W,         PDYN:p.G191W, PDZD2:p.R565S, PDZD8:p.S980G, PFKM:p.R118S,         PIGM:p.R225L, PIK3CA:p.E542K, PIK3CG:p.V165L, PLLRA:p.S291fs,         PLCE1:p.G564C, PLCL1:p.M564I, PLEKHA6:p.R110L, PNKP:p.G174W,         POGZ:p.G75W, POLE:p.R573L, POM121L12:p.P231T, POM121L12:p.P242H,         POTEE:p.V288M, POTEM:p.S78R, POU3F3:p.D321Y, PPT2:p.R265L,         PRDM16:p.P1036L, PRELP:p.D201Y, PRPF40B:p.R160S, PRPF6:p.R763L,         PTEN:p.R234L, PTPN11:p.G503V, PTPN13:p.E2067K, PTPRJ:p.G334W,         PTPRT:p.R928L, PTPRU:p.P559S, PXDNL:p.P1456T, QSOX1:p.R401L,         QSOX2:p.R683L, RAB13:p.R167L, RAB8A:p.G20W, RAPGEFL1:p.R356L,         RBM19:p.G390W, RCL1:p.P112Q, REG1B:p.W57L, REG3A:p.S150L,         REG4:p.G110V, RIMS2:p.R55L, RIT2:p.R85L, RLN2:p.S138C,         RNF20:p.P529Q, RORB:p.G94W, RPL10L:p.K187T, RPRD2:p.R97S,         RTN1:p.S103W, RUNX2:p.R337M, RYR2:p.K2413N, RYR2:p.M4334I,         RYR3:p.P1670T, S100PBP:p.R5L, S1PR1:p.L104F, SAGE1:p.H298Q,         SALL1:p.E965K, SALL1:p.R898W, SALL4:p.R187L, SBSPON:p.G133W,         SCAF8:p.G740C, SCG2:p.P252Q, SCML4:p.L261F, SCN2A:p.T155K,         SEC24D:p.A50fs, SEC61A2:p.G126V, SERPINA12:p.D253Y,         SERPINA9:p.M414I, SERPINC1:p.R45L, SGIP1:p.R502L,         SH3GL3:p.R174L, SH3PXD2A:p.S759L, SI:p.V1217F, SKOR1:p.Y883C,         SLC1A2:p.F348fs, SLC24A5:p.R35S, SLC25A48:p.R101S,         SLC35E2:p.R201L, SLC39A12:p.C628S, SLC39A6:p.R53L,         SLC4A5:p.I533V, SLC5A1:p.G53W, SLC5A7:p.G442V, SLC6A11:p.W299L,         SLC6A2:p.5354C, SLC8A1:p.G433C, SLIT1:p.R1460L, SLITRK5:p.R68L,         SLITRK5:p.R468M, SLITRK6:p.N741K, SORL1:p.R205L, SOS1:p.N233Y,         SOX9:p.E75K, SPAG16:p.V439L, SPIN4:p.Y171C, SPRR2D:p.P30fs,         SPTA1:p.G2367C, SPTA1:p.D2243Y, SSX3:p.P127T, ST18:p.H778Q,         STAC3:p.G117W, STOML3:p.D86Y, STX2:p.R107L, SUMF2:p.G110E,         SUN3:p.P339Q, SV2C:p.P60Q, SYNDIG1:p.D135Y, SYNE1:p.K8632E,         TARS2:p.E199K, TAS2R16:p.Q177H, TCOF1:p.K264R, TCTE1:p.S127I,         TDO2:p.Q197H, THSD7A:p.G810W, THSD7A:p.R801L, TIFAB:p.D43E,         TIGD4:p.S312F, TLL1:p.P53Q, TMPRSS11E:p.G259C, TMTC1:p.A864D,         TMTC1:p.G212V, TMX3:p.R51C, TNNI1:p.R67L, TNR:p.L692I,         TOP2A:p.R736L, TP53:p.R337L, TP53:p.E285K, TP53:p.R283P,         TP53:p.D281N, TP53:p.C277F, TP53:p.V274F, TP53:p.R273H,         TP53:p.I255F, TP53:p.R249S, TP53:p.M237I, TP53:p.S215I,         TP53:p.C176F, TP53:p.R10L, TP53:p.G105C, TP53:p.P72fs,         TPO:p.E558K, TRAF6:p.R502S, TRIM42:p.Q127K, TRIM48:p.A93D,         TRIM4:p.R398L, TRIM51:p.W131C, TRIM9:p.R337S, TRIML:p.H399Q,         TRPM3:p.G298W, TSC1:p.G378C, TSG101:p.R276S, TSHZ1:p.K501N,         TSHZ3:p.G677V, TTF2:p.R761S, TUBA3C:p.Q176fs, UBAC1:p.K330N,         UBE2J2:p.G193W, UBR1:p.G1647W, UGT2B7:p.M214I, VMP1:p.E369Q,         VPS13B:p.G2575W, VSTM2A:p.G75V, VWA3B:p.R557L, WBP11:p.P227fs,         WDR52:p.G612C, WDR59:p.R837S, WDR75:p.P287Q, WDR88:p.G100W,         ZCCHC5:p.G335W, ZFHX4:p.L811F, ZFHX4:p.T1663N, ZFHX4:p.H2511Q,         ZFP14:p.Q17L, ZIC1:p.A112E, ZNF154:p.T408N, ZNF223:p.G23W,         ZNF295:p.S732C, ZNF322:p.K106N, ZNF385D:p.T226S, ZNF454:p.S190I,         ZNF492:p.P392H, ZNF521:p.G640C, ZNF521:p.P270H, ZNF536:p.G186C,         ZNF536:p.G663W, ZNF644:p.G21W, ZNF716:p.H263L, ZNF71:p.V411L,         ZNF782:p.G484W, ZNF831:p.Q617K, ZNF98:p.C492F, and         ZSWIM2:p.S214Y.

54. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from LUSC; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         PIK3CA:p.E545K, TP53:p.R158L, KRTAP5-5:p.GCG47del,         NFE2L2:p.E79Q, CDKN2A:p.D108Y, DHX9:p.V40G, MAFA:p.207_208HH>H,         NFE2L2:p.R34Q, PBX2:p.Y262F, PIK3CA:p.E542K, TP53:p.R273L,         TP53:p.C242F, TP53:p.R175G, TP53:p.Y163C, TP53:p.V157F,         AICDA:p.R131G, ALPK2:p.D53N, ANKFN1:p.M280I, ARPC1A:p.F212L,         ASXL2:p.S1081L, C1orf74:p.D254N, C3orf30:p.D227E,         CCDC121:p.W397L, CHN2:p.143M, CLEC4C:p.R179L, CLN3:p.G206S,         CNTN5:p.T178N, COL2A1:p.G2753C, CPS1:p.T855K, CSMD3:p.T1094K,         CSMD3:p.Q691K, DDX11:p.R167T, EGFR:p.L861Q, EME1:p.D570H,         EP300:p.D1399N, ESYT3:p.S574F, FAM135B:p.L648M, FAM135B:p.Q285H,         FAM47A:p.G372W, FBXW7:p.R505G, FGFR3:p.S249C, GALNT13:p.G358C,         GNL3L:p.K20N, GPC5:p.R347L, HCN1:p.A714S, HCN1:p.R659L,         HCN1:p.G499V, HCN1:p.P326T, HERC2P3:p.A803V, HEXDC:p.T482P,         HIST1H3B:p.E74K, HIST2H2BE:p.G54D, IFNA10:p.V79A, IL7R:p.S54L,         INADL:p.P1340A, ISX:p.C2F, ITGAX:p.R685H, ITPR1:p.E1883Q,         KCNN3:p.80_81insQQ, KEAP1:p.G480W, KEAP1:p.R470C, KEAP1:p.V155F,         KIAA1751:p.L63F, KIAA2022:p.C345F, KIR3DL2:p.K229E,         KLF5:p.E419Q, LAMA4:p.M1293I, LMLN:p.G199C, LRP2:p.A516V,         LRRC66:p.F458L, LSG1:p.R517L, LUM:p.R310L, MB21D2:p.Q311E,         MCHR1:p.S306F, MKRN3:p.G270V, MUC16:p.N11594K, NFE2L2:p.G81S,         NFE2L2:p.G31A, NFE2L2:p.L30F, NFE2L2:p.D29H, OR2B11:p.G10V,         OR2T2:p.F13V, OR4K2:p.C254F, OR51F2:p.R67P, OR51S1:p.R159Q,         OR5D18:p.T271K, OR8H2:p.L166F, OR8J3:p.S160L, OR8K3:p.K235N,         PCDHB1:p.N568K, PHIP:p.I1681M, PIK3CA:p.E726K, PIK3CA:p.H1047R,         PLCE1:p.G439C, PRSS57:p.E39Q, PYHIN1:p.G148A, RANBP6:p.I984L,         RBMXL1:p.G305C, REG1B:p.M67I, RGS6:p.W366L, RNF5:p.T136I,         RP1:p.S1771L, RRP15:p.L214F, RYR2:p.E711K, SAMD3:p.Q206H,         SLITRK3:p.R214L, SON:p.S908L, SP4:p.E1 del, STK11:p.G279fs,         TARBP1:p.L782V, TBCD:p.R476C, TMPRSS11F:p.R274Q, TP53:p.R337L,         TP53:p.E271K, TP53:p.R267P, TP53:p.G245V, TP53:p.Y234C,         TP53:p.Y220C, TP53:p.H214R, TP53:p.H193L, TP53:p.H179L,         TPTE:p.M541I, TRIM7:p.L332I, TTN:p.T32425M, ZFP36L2:p.D240N,         ZNF208:p.H883Q, ZNF48:p.R235H, ZNF626:p.K473R, ZNF676:p.P43T,         ZZZ3:p.R162Q.

55. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from OV; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         TP53:p.R273H, TP53:p.Y220C, TP53:p.R248Q, TP53:p.R175H,         TP53:p.R273C, TP53:p.1195T, TP53:p.R248W, TP53:p.R282W,         TP53:p.C176Y, TP53:p.V157F, TP53:p.S241F, TP53:p.H179R,         TP53:p.G245S, TP53:p.H193R, ADCY2:p.V888I, B2M:p.M1V,         BAP1:p.R227C, CYP4A11:p.V185F, DNAH5:p.R3197Q, GART:p.K807fs,         GRIN2B:p.R519Q, HRNR:p.M1fs, KLHL29:p.L716fs, KRAS:p.G12V,         MGA:p.R2435Q, MYO3A:p.N525S, NPAS2:p.Q201R, NRAS:p.Q61R,         PDAP1:p.K55fs, PGAP1:p.F565C, TP53:p.S315fs, TP53:p.C275Y,         TP53:p.R273L, TP53:p.V272M, TP53:p.G266V, TP53:p.G266R,         TP53:p.D259Y, TP53:p.P250L, TP53:p.G245D, TP53:p.G245V,         TP53:p.G244C, TP53:p.C238fs, TP53:p.Y236C, TP53:p.Y234C,         TP53:p.V216M, TP53:p.S215R, TP53:p.Y205C, TP53:p.L194R,         TP53:p.P191del, TP53:p.Y163C, TP53:p.A159V, TP53:p.K132N,         TRPC7:p.D210V, UXS1:p.V100L, WNT11:p.C344Y, and ZNF295:p.E885A.

56. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from READ; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         KRAS:p.G12V, TP53:p.R273H, KRAS:p.A146T, KRAS:p.G12D,         TP53:p.R175H, AKAP9:p.L3482I, APBA1:p.E624K, BAG5:p.D439N,         C17orf97:p.E230D, CDH23:p.F177L, CERS3:p.E95D, DNAH5:p.R982H,         ERBB2:p.V842I, GABRB3:p.D500N, KRAS:p.G13D, KRAS:p.G12C,         KRAS:p.G12S, LRP6:p.R675Q, MACF1:p.F722L, MBOAT2:p.R43Q,         MYO1D:p.E246K, NLRC4:p.E409K, NRAP:p.E327K, NRAS:p.Q61K,         PCDH15:p.R1552I, PIK3CA:p.N345K, PIK3CA:p.E545K, POLE:p.S459F,         PPP2R2B:p.P326L, SMAD4:p.R361H, TP53:p.R248W, ZFP2:p.R150I, and         ZNF563:p.K26N.

57. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from SKCM; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         BRAF:p.V600E, NRAS:p.Q61R, NRAS:p.Q61K, HSD17B7P2:p.N175S,         BRAF:p.V600K, DISP1:p.G732L, IDH1:p.R132C, NRAS:p.Q61L,         MUC16:p.P5119S, RAC1:p.P29S, WASH3P:p.G175S, AGAP9:p.M248V,         C15orf23:p.S24F, DNAH5:p.D3236N, SPTLC3:p.R97K, TMC5:p.R276C,         CFB:p.R314M, FRG1B:p.A50P, INMT:p.S212F, LOC649330:p.G93E,         MAP2K1:p.P124S, RGS7:p.R44C, STK19:p.D89N, ADAM30:p.G97L,         ARL16:p.G6R, ARMC4:p.E22K, BRAF:p.K601E, CAPN13:p.P405S,         CD1C:p.R89C, CLCC1:p.P406Q, CNTN5:p.S379F, DNAH5:p.R742Q,         EEF1B2:p.S43G, FRG1B:p.I59V, GABRG1:p.E205K, IARS2:p.R832C,         IL32:p.D218fs, ISX:p.R86C, KLHDC7A:p.E635K, NAP1L4:p.P285Q,         NBPF10:p.Q908E, OR2A5:p.S71L, OR4E2:p.R226Q, OR4M1:p.G41E,         OR4M2:p.S268F, OR4N2:p.G41E, OR51B2:p.S163L, PCDHGC5:p.R293C,         PCLO:p.R4133C, PHGDH:p.G173L, POTEG:p.D51N, PPP6C:p.R301C,         PRAMEF11:p.C84S, PSG9:p.E404K, PTPRB:p.D1560N, RNF152:p.P95S,         SPAG16:p.P488S, SPATA8:p.E18K, TAF1A:p.R172M, TCEB3C:p.E308K,         THSD7B:p.E126K, TTN:p.E12129K, XIRP2:p.D2439N, and         ZNF831:p.R1393Q.

58. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from UCEC; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         RPL22:p.K15fs, PTEN:p.R130G, PTEN:p.R130Q, KRAS:p.G12D,         KRAS:p.G12V, PIK3CA:p.H1047R, PIK3CA:p.R88Q, PIK3CA:p.E545K,         PTEN:p.V317fs, FGFR2:p.S252W, PIK3CA:p.E542K, CTNNB1:p.S37F,         POLE:p.P286R, PPP2R1A:p.P179R, CTNNB1:p.S37C, KRAS:p.G13D,         CTNNB1:p.D32N, CTNNB1:p.S33F, CTNNB1:p.G34R, KIAA2026:p.R574C,         LIMCH1:p.R806fs, PIK3CA:p.H1047L, ALPK2:p.K523fs, CTNNB1:p.S33C,         FBXW7:p.R505C, HPD:p.R284fs, KRAS:p.G12A, PIK3CA:p.R93Q,         POLE:p.V411L, TP53:p.R248W, ABCA11P:p.R385I, ABI1:p.K445N,         ACSM2B:p.K195N, APOB:p.F3102L, ASCC3:p.R136Q, C12orf4:p.R335Q,         CCDC132:p.R838C, CHD4:p.R975H, CSDE1:p.R220C, CTNNB1:p.D32Y,         CTNNB1:p.S33Y, CTNNB1:p.T41I, EXOC1:p.R588C, FBXW7:p.R465H,         FGFR2:p.N549K, FUBP1:p.R430C, GEN1:p.S509L, IK:p.E90fs,         KIF20B:p.E54K, MAX:p.H28R, MBOAT2:p.R43Q, METTL14:p.R298P,         MFGE8:p.D170N, MS4A8B:p.S3L, NSMCE1:p.D244N, OXR1:p.E122K,         PCDH19:p.E530K, PIK3CA:p.R108H, PIK3CA:p.N345K, PIK3CA:p.C420R,         PIK3CA:p.Q546P, PIK3CA:p.Q546R, PTEN:p.R130L, RBL2:p.E127K,         RXFP1:p.S223Y, SF3B1:p.R957Q, SLC20A1:p.P328fs, SOX17:p.S403I,         TNS1:p.Q659del, TP53:p.R273H, TP53:p.R273C, TP53:p.R248Q,         TTN:p.D16823N, TXNL1:p.R234C, ZFHX3:p.R1893fs, ZNF180:p.R625I,         ZNF257:p.R392I, ZNF354B:p.D609N, ZNF43:p.R280C, ZNF709:p.R468L         ZNF765:p.S254L, ABCA5:p.R1476Q, ACVR1:p.R206H, ADAD1:p.S11L,         ADAM9:p.R256Q, ADD3:p.E570K, ADGB:p.S1124L, AGXT2:p.R502C,         AMBN:p.S225Y, ANKDD1A:p.R24H, ARHGEF33:p.R46I, ATP10B:p.L1304I,         ATP2C1:p.E724K, ATP9A:p.R290Q, ATR:p.R1814fs, AVL9:p.F34L,         BMPER:p.R241Q, BTN3A2:p.E153K, C14orf118:p.R279I,         C14orf166B:p.F230L, C3orf23:p.R217C, C3orf62:p.R185Q,         CACNA1C:p.S710L, CAGE1:p.E539K, CARD10:p.KE272del,         CCDC144A:p.S1264L, CCDC168:p.D5020Y, CCDC36:p.R209I,         CD55:p.E156K, CEP44:p.S253L, CIITA:p.E728K, CREBBP:p.P2094L,         CTNNB1:p.S37A, CTTNBP2:p.S420L, DCT:p.R532Q, DIAPH2:p.E121K,         DLG2:p.S624L, DNAH10:p.R1888Q, DNAH14:p.R1367C, DNAH7:p.R2961Q,         DNAH8:p.R1347H, DNAJC13:p.E1248K, DNMT1:p.E51K, DST:p.S767Y,         DYNC2H1:p.E883D, EMR1:p.R631Q, EPHX4:p.R282Q, ERCC6L2:p.L445I,         F10:p.E117K, FAM155B:p.E158K, FAM83B:p.R206Q, FARP1:p.S383L,         FAT3:p.A4159T, FBXW7:p.R689W, FBXW7:p.R465C, FBXW7:p.G423V,         FN1:p.R290C, FZD6:p.R416Q, GABRA3:p.R73H, GABRA4:p.R460Q,         GALNTL2:p.E395K, GFAP:p.A233T, GGA2:p.A63V, GIGYF2:p.R227H,         GNPTAB:p.R1189Q, GPR112:p.S1283Y, GPR98:p.R4142W, GRIA3:p.S646Y,         GRM6:p.E363D, HMCN1:p.S133Y, HSPA4L:p.R483C, HTR2A:p.S219L,         INTS7:p.R940C, INTS7:p.R106I, ITM2C:p.E167K, JAKMIP2:p.R283I,         KCND3:p.S438L, KCNS2:p.D211N, KDM1B:p.F361L, KIAA0556:p.L330I,         KIAA1147:p.A149V, KIF23:p.R150Q, KIF27:p.K925N, KIF9:p.R594Q,         KLHL13:p.E213K, KLHL28:p.E33K, LIN9:p.R183W, LRBA:p.E2103K,         LRP2:p.R2432I, MAGI2:p.L450M, MC5R:p.A109T, MEGF10:p.S1053L,         MKI67:p.T1664fs, MKLN1:p.F485L, MMRN1:p.F917L, MSH4:p.E730K,         MTOR:p.S2215Y, MUC7:p.S336L, MYBPC2:p.R646H, N4BP2L2:p.R506C,         NAPSA:p.R121Q, NCOA7:p.E369D, NCR1:p.R258W, NEK11:p.R374Q,         NHEJ1:p.R109Q, NNMT:p.E233K, NOTCH4:p.15_16LL>L, NPY1R:p.A371T,         NRAS:p.Q61R, OGDHL:p.R57C, OMA1:p.R445Q, OPRM1:p.R462C,         OR4C12:p.F248L, OR5AK2:p.K89N, OSBPL6:p.R577Q, PCDHAC2:p.K138N,         PCDHB12:p.R289C, PCDHGC5:p.A70T, PIK3CA:p.R38H, PIK3CA:p.E39K,         PIK3CA:p.E110del, PIK3CA:p.K111E, PIK3CA:p.Q546K,         PIK3CA:p.M1043V, PIK3CA:p.M1043I, PLA2G3:p.R201Q,         PLXNA1:p.E1295K, PON1:p.R306Q, POTEE:p.R303I, POTEF:p.K674N,         PPP2R1A:p.S256F, PPP2R3B:p.F310L, PRAM1:p.A268T, PREX1:p.E1246K,         PRKCQ:p.A324V, PTEN:p.R130P, PVRL4:p.A358T, RAI2:p.S385Y,         RBM39:p.T353I, RELN:p.F2722L, RFPL1:p.R148Q, ROBO2:p.D1018N,         ROS1:p.R245I, RPS6KA6:p.S394Y, RSBN1:p.E572K, RYR1:p.A2576T,         SACS:p.R2906Q, SCAPER:p.R366Q, SELP:p.R429W, SENP7:p.S673Y,         SEPHS1:p.E13K, SFRP4:p.R232Q, SGK1:p.K367del, SIX1:p.E191K,         SLC10A7:p.S261L, SLC12A2:p.R828Q, SLC6A4:p.R495Q,         SLC7A2:p.R322W, SMCR8:p.E175K, SOS1:p.N233Y, SPOP:p.E50K,         STRN3:p.K218N, STXBP6:p.D92N, SULT1E1:p.R77Q, SUN3:p.L124I,         SUSD1:p.R343C, SYNM:p.R516Q, TAF1:p.R843W, TDRD3:p.R322Q,         THADA:p.S1941L, TLN2:p.S208L, TMEM161B:p.R315Q, TMPRSS3:p.R16Q,         TP53:p.Y220C, TPTE:p.S423L, TRANK1:p.E846K, TRPC5:p.S490L,         TRPM3:p.R429W, TSSK1B:p.E301K, TTLL7:p.R751H, TTN:p.S20317L,         TTN:p.E6404K, TTN:p.R4434Q, TTN:p.R2506Q, UGT8:p.E102K,         USF1:p.R52Q, USP16:p.R455Q, USP25:p.R873H, USP33:p.R36Q,         VPRBP:p.R802Q, VPS3B:p.R692Q, WDR65:p.F110C, YTHDC2:p.E185K,         ZFYVE1:p.R266Q, ZKSCAN1:p.R541fs, ZNF117:p.R157I,         ZNF180:p.R569I, ZNF195:p.R59Q, ZNF254:p.K179N, ZNF263:p.R510I,         ZNF333:p.R554Q, ZNF354B:p.R402I, ZNF442:p.R309Q, ZNF454:p.R376I,         ZNF485:p.R374I, ZNF488:p.R206Q, ZNF559:p.E284K, ZNF594:p.R287I,         ZNF611:p.R390I, ZNF645:p.R154C, ZNF649:p.R338Q, ZNF649:p.R198I,         ZNF674:p.R405I, ZNF675:p.R220I, ZNF678:p.R564I, ZNF732:p.R354I,         ZNF780A:p.R466Q, ZNF823:p.R547I, ZNF836:p.R854I, ZNF836:p.R630I,         ZNF841:p.R757I, and ZNF98:p.R3701.

59. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from ACC; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         ZFPM1:p.EPL444del, GARS:p.P42A, ZNF517:p.V349A, LRIG1:p.L24V,         CCDC102A:p.R96W, OPRD1:p.C27F, SOWAHA:p.R124P, LACTB:p.M5L,         TOR3A:p.F13L, ZFPM1:p.E444fs, ZNF787:p.D367del, LRIG1:p.L26V,         IRX3:p.L422P, TRIOBP:p.H1300R, TUBA1C:p.L146F, ZFPM1:p.P445fs,         ZFPM1:p.446_447LA>P, TPO:p.S398T, USP42:p.R779P, ERCC2:p.D312N,         GLTPD2:p.D209E, OTOP1:p.LLW 104del, RINL:p.P402L, AMDHD1:p.S3G,         ASPDH:p.Q266R, KCNK17:p.S21G, TMEM247:p.Q128E, MUC5B:p.D682G,         OBSCN:p.R4516W, FAM184B:p.R784W, SEMA5B:p.V840D, ZNF598:p.E25G,         ADAD2:p.G44E, C1orf106:p.R538C, ZAR1:p.Q42H, PANK2:p.G126A,         PODXL:p.28_30PSP>P, SALL3:p.L593V, THEM4:p.L17R,         C2orf81:p.T315P, CLDN23:p.V210M, FAM109A:p.GGG156del,         FPGS:p.122V, HHIPL1:p.V692A, MUC5B:p.M2869T, PLEC:p.R1386Q,         SYT8:p.R373W, TAF5:p.S130A, TMEM189-UBE2V1:p.N6D, UQCRFS1:p.S6A,         B3GNT6:p.L316fs, CCDC105:p.P499T, CLIC6:p.Q298E, IDUA:p.T374P,         NOTCH2:p.C19W, RGS9BP:p.A96S, RREB1:p.G783V, SP8:p.G165del,         WDR34:p.W60G, C19orf10:p.G12R, CELSR2:p.16_17insP,         FAM75C1:p.71_71H>HLVSQRH, GPRIN2:p.R446H, KBTBD13:p.A81V,         OGFR:p.S557T, PODXL:p.30_30P>PSP, BHLHE22:p.L62Q,         C4orf32:p.G32E, C5orf65:p.Q245R, KNDC1:p.V806D,         KRTAP10-6:p.49_49P>PSCCAP, LRP11:p.P92R, MAP1S:p.S411C,         NOL9:p.S58A, RASIP1:p.R601C, RGMB:p.S63R, SARM1:p.R23P,         TSC22D2:p.A419T, ZNF628:p.T230A, ZNF814:p.A337V, AATK:p.A541T,         BTBD11:p.G265A, CRIPAK:p.C143R, KCTD3:p.F9V, KRT8:p.S59A,         MUC5B:p.S681G, NCOR2:p.1846_1847insSSG, OGFR:p.E556K,         APOE:p.C130R, C10orf95:p.A85S, C13orf33:p.R59G, CRIPAK:p.C174R,         FAM18B2:p.C51Y, GLI3:p.P998L, GLTSCR2:p.Q389R, HECTD2:p.P19A,         IRF2BPL:p.123_125QQQ>Q, MEX3C:p.179_182AAAA>A, NEFH:p.EE658del,         RNF49:p.S9G, RNF222:p.A133T, SEZ6L2:p.R74P, TNIP2:p.R73G,         ARRDC4:p.T79A, B3GNT6:p.P330fs, BAG1:p.G45R, C22orf26:p.P28L,         CHDH:p.E40A, COQ2:p.V66L, CTGF:p.H83D, DLEU7:p.A83V,         EPPK1:p.D2378H, FAM86C1:p.R30P, FZD1:p.93_94insP,         GPRIN2:p.V241M, GPX1:p.11_13AAA>A, HES3:p.P96T, JMJD4:p.A11V,         KANK3:p.R359H, LPPR2:p.A186S, NEFH:p.665_666insEE, NOM 1:p.R24G,         RNF39:p.G263C, SCRT1:p.S133A, SNED1:p.L1228P,         TTLL11:p.122_123insKA, ZCCHC3:p.A159del, ZNF219:p.QP233del,         ASB16:p.T249A, ASB2:p.H515P, ATP9B:p.S39G, AVL9:p.G7fs,         C17orf96:p.L63V, C19orf29:p.A499V, CRB2:p.T1110M,         CRIPAK:p.P173R, CRIPAK:p.I190L, CSGALNACT2:p.L362F,         CTBS:p.LAL31del, CTNNB1:p.S45P, DMRT1:p.S45T, DOK7:p.G461D,         FBRSL1:p.A836V, FEZ2:p.P50L, FRG1:p.S169N, HSD17B1:p.G313S,         IBA57:p.S130R, KIF1A:p.E917D, KRTAP9-1:p.160_160Q>QPSCGSSCCQ,         LURAP1L:p.55_56insGGG, NMU:p.A19E, NMU:p.A18E, NOXA1:p.D6E,         NPTX1:p.G100D, PLIN5:p.R306W, TBP:p.95_96insQ, TMEM200C:p.S498G,         TNXB:p.V706fs, VARS:p.P51S, ZC3H12D:p.P405S, and ZZEF1:p.V30A.

60. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from CESC; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         PIK3CA:p.E545K, PIK3CA:p.E542K, MAPK1:p.E322K, EP300:p.D1399N,         ERBB2:p.S310F, ERBB3:p.V104M, KRAS:p.G12D, ANKRD12:p.E721Q,         ANKRD36:p.M1144T, MICA:p.G318fs, PIK3CA:p.E726K, PTEN:p.R130Q,         ABCD1:p.S606P, ACTL7B:p.E211K, ADAM21:p.F129C,         ADAMTS12:p.P1053A, AKT1:p.E17K, ANKLE1:p.V643L, ANO3:p.M956I,         AOAH:p.R326T, APOD:p.S115L, ASCC1:p.H207Y, ATM:p.S800F,         AURKA:p.S387L, BAG5:p.M286I, C12orf43:p.E28Q, C16orf3:p.G65S,         C3orf70:p.S6L, C4orf21:p.E800Q, CALB2:p.K60N, CALCB:p.R81T,         CCDC152:p.E153Q, CCDC53:p.R58C, CDC27:p.P242S, CFHR5:p.R441H,         CLOCK:p.L123fs, CMYA5:p.E2733K, CNTRL:p.P185S, CSHL1:p.R117Q,         CSMD3:p.H952Y, CTNNB1:p.D32G, CTSH:p.E254Q, DHPS:p.F49L,         DMPK:p.R44H, DNAH14:p.F622fs, DNAH3:p.E3367Q, DNAH8:p.E587D,         DNASE1L1:p.D212N, ECE2:p.D254N, FAM71B:p.H445D, FAM73A:p.G23V,         FAS:p.E261K, FBXW7:p.R505G, FBXW7:p.R465C, FEZF2:p.E82K,         FKBPL:p.E161Q, FMNL1:p.E927Q, GPATCH3:p.E275Q, GPR142:p.R304T,         GPRIN2:p.T100P, GRAMD2:p.II23M, HERC2:p.S329F, HGF:p.G229A,         HIF3A:p.A72T, HIST1H1B:p.K188N, HIST1H2AL:p.R30P,         HIST2H2AC:p.R30P, HLA-C:p.N104K, HLA-DPB1:p.G114fs,         HRNR:p.G2539S, INVS:p.R799K, JPH3:p.Q433H, JUP:p.S627L,         KIAA1211:p.R308fs, KIAA1211:p.E309fs, KLK2:p.E161K, KRAS:p.G13D,         KRAS:p.G12V, LIN9:p.E231K, LOC151174:p.P90S, LRRC37A3:p.A406D,         LRTM2:p.L176V, MEPE:p.S30T, MUC12:p.R2634C, MUC4:p.S2936L,         MYOM2:p.D988N, NFE2L2:p.D29H, NOTCH2:p.R2298W, NPIPL1:p.P250L,         NR5A2:p.E80K, NYAP2:p.R197Q, OBSL1:p.E1642K, OR13C2:p.L9V,         OSBP:p.Q721H, PAOX:p.H107Y, PDILT:p.E500K, PIAS3:p.D460N,         PLEKHO2:p.E351Q, PNRC1:p.R73C, PPP4R1:p.L597F, PREP:p.F469L,         PRKDC:p.Q3568E, PSME3:p.R231W, RANBP6:p.R915W, RCAN2:p.D440N,         RNPC3:p.E116fs, SDHAP1:p.H66Y, SDHAP2:p.S37fs, SERPINA3:p.K158N,         SERPINA4:p.R98C, SF1:p.R255W, SGSM1:p.E818K, SIM1:p.V213M,         SLC10A4:p.F281L, SLC25A5:p.I79F, SLC35G2:p.K62fs,         SLC4A9:p.R617C, SLCO2A1:p.M479I, SND1:p.Q38E, SPATA17:p.R72K,         SRSF12:p.S150C, TADA2B:p.E67K, TCTEX1D2:p.S74L, TEDDM1:p.M166I,         TEX15:p.E1652Q, TMC2:p.E92D, TMEM131:p.E1319Q, TNKS2:p.T619fs,         TNS1:p.Q659del, TP53:p.E285K, TRAF3:p.S9F, TRIM61:p.K98N,         TRPM1:p.M996I, TUFT1:p.L101F, U2AF1:p.S34F, UNC93B1:p.V498M,         USP4:p.L259V, VCAN:p.S1308C, WDR17:p.P278S, ZBED4:p.S385L,         ZEB2:p.E1094K, ZFYVE9:p.M1147I, ZNF16:p.R452W, ZNF677:p.R131T,         and ZSWIM4:p.E407K.

61. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from CRC; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         KRAS:p.G12D, KRAS:p.G12V, BRAF:p.V600E, KRAS:p.G13D,         TP53:p.R175H, PIK3CA:p.E545K, FBXW7:p.R465H, KRAS:p.A146T,         PIK3CA:p.H1047R, TP53:p.R248W, CDC27:p.D555E, SMAD4:p.R361H,         TP53:p.R273H, KRAS:p.G12C, NRAS:p.Q61K, ERBB2:p.V842I,         ERBB3:p.V104M, FBXW7:p.R465C, PIK3CA:p.R88Q, PIK3CA:p.E542K,         TP53:p.R273C, TP53:p.G245S, AXIN2:p.G665fs, C16orf45:p.T106N,         C20orf26:p.R1088Q, DNMT1:p.E432K, FBXW7:p.R505C, HLCS:p.E362K,         HPSE2:p.K58N, KIF14:p.R598Q, KIF18A:p.R17C, KIF20B:p.E991K,         KLHL5:p.R326C, KLK2:p.P57T, KRAS:p.G12A, KRAS:p.G12S,         LPHN3:p.R1183Q, LRP6:p.R675Q, MYH8:p.R1048Q, NRAP:p.E327K,         NRAS:p.G12C, PIK3CA:p.N345K, POSTN:p.R508C, PPP2R1A:p.R183W,         PTEN:p.R130Q, RAF1:p.S257L, SDK1:p.T1181M, SGSM1:p.F1117L,         TCF7L2:p.R482fs, TP53:p.R282W, TRIM23:p.R289Q, UGT8:p.E102K,         ZNF491:p.R343Q, A2M:p.R732Q, AADACL4:p.A266T, ABCA8:p.E1158K,         ABCA8:p.R842Q, ABCA8:p.A696T, ABCB8:p.R345H, ACACA:p.R1731C,         ACADM:p.F48C, ACOT9:p.R50Q, ACPP:p.R105Q, ACTL7B:p.R354H,         ACTL9:p.R331H, ACVR1:p.S290L, ADAM30:p.S314Y, ADAM32:p.R559Q,         ADAMTS16:p.D817N, ADAMTS4:p.R156W, ADCY5:p.R661H, AGMAT:p.V313M,         AGPAT4:p.A212T, AKAP12:p.E1282K, AKAP9:p.L3482I, ALB:p.S294L,         ALDH1L1:p.A870T, ALG2:p.S302Y, AMOTL1:p.R676Q, AMPD1:p.K502N,         AMPH:p.R292W, ANKRD6:p.R479C, APBA1:p.K730N, APBA1:p.E624K,         APC:p.E847fs, APC:p.F1354fs, APC:p.M1413fs, APOB:p.R3136C,         APOB:p.A43V, APPL1:p.R668W, AQPEP:p.A309T, ARF4:p.R149H,         ARFGEF1:p.D1632N, ARHGAP32:p.E1253K, ARHGAP36:p.R128C,         ARHGAP36:p.A147V, ARHGAP5:p.D890fs, ARNTL:p.T395M,         ARPP21:p.R338H, ARSG:p.V131I, ASCC3:p.R1197Q, ATP10D:p.R311H,         ATP6V0A4:p.R191Q, ATP9B:p.R265Q, AXDND1:p.E930D, AXIN2:p.W663fs,         B2M:p.L13fs, B3GALNT1:p.R145Q, BACH 1:p.R538Q, BAG5:p.D439N,         BBOX1:p.F176V, BCL2L11:p.R91Q, BCL7A:p.T52M, BCLAF1:p.R37fs,         BEND5:p.R198C, BICD2:p.R162H, BLVRA:p.S44L, BMP3:p.R344W,         BNC2:p.R512W, BRPF1:p.R66C, BRWD3:p.R787C, BTBD7:p.S436L,         BUB1B:p.F996L, BZRAP1:p.V1627I, C11orf330:p.R111C,         C14orf101:p.E295K, C14orf102:p.D115N, C14orf105:p.R100I,         C15orf2:p.V488I, C15orf33:p.D340N, C16orf87:p.R151I,         C1RL:p.L351fs, C22orf40:p.P32fs, C3orf39:p.R333W, C5orf30:p.D4N,         C5orf4:p.R114Q, C6orf170:p.K724T, C7orf63:p.A10T,         CACHD1:p.S720Y, CACNA1A:p.T665M, CACNA2D3:p.A332T,         CACNB2:p.R608H, CACNG3:p.V134I, CACNG3:p.A138V, CACNG5:p.G121R,         CADM1:p.S190L, CADP5:p.A1073T, CAPRIN2:p.E13K, CARD11:p.R423Q,         CASC1:p.R54Q, CASP14:p.RSW, CBFB:p.E152K, CC2D2A:p.R1284C,         CCDC18:p.K615N, CCDC60:p.R230H, CCDC81:p.R259I,         CCDC88C:p.P1851fs, CCKBR:p.V236M, CD101:p.D283Y, CD101:p.R594Q,         CD180:p.N228T, CDC14B:p.R375C, CDCA7L:p.P405fs, CDH10:p.E349K,         CDH12:p.D674N, CDH20:p.A134V, CDH23:p.F177L, CDH2:p.D547Y,         CDH9:p.F523L, CDK16:p.R108C, CEACAM5:p.L640I, CEP152:p.E21K,         CERS3:p.E95D, CHD4:p.R975H, CHD5:p.A801T, CIZ1:p.V668A,         CLEC18A:p.R423H, CLTCL1:p.R481W, CMAS:p.R110Q, CNRIP1:p.R102W,         COBLL1:p.K732N, COL4A1:p.R1082I, COL17A1:p.P1004L,         COL4A6:p.L550I, COL6A3:p.D2792N, COPB1:p.R425C, CORO2A:p.*526R,         COX15:p.L86I, CSMD1:p.S781Y, CTCFL:p.E423K, CTDNEP1:p.E126K,         CTTNBP2:p.R164C, CYP4B1:p.E434D, DACH2:p.R539C, DBC1:p.V216I,         DBF4B:p.S254Y, DCHS2:p.F2149L, DCLK2:p.S549Y, DDI1:p.R275Q,         DENND4A:p.P357H, DENND4C:p.R1081Q, DHTKD1:p.R410Q,         DISP1:p.R763C, DKK2:p.R230H, DKK4:p.R203Q, DLC1:p.A350V,         DLC1:p.E222D, DMD:p.R3195H, DNAH5:p.R982H, DNAH5:p.R224Q,         DNAH9:p.D1547N, DNAJC24:p.E61K, DNM1:p.A251T, DNMT1:p.E1531Q,         DNMT3B:p.R92W, DOCK10:p.A1830V, DOCK1:p.E864K, DOCK2:p.G170R,         DOCK3:p.R1183C, DOCK5:p.E177K, DOK5:p.R274W, DPP8:p.G165R,         DPY19L1:p.F378L, DUOX2:p.F880L, DVL2:p.A601fs, EBAG9:p.E187K,         EBF3:p.G255fs, EDNRB:p.L450R, EGR2:p.R390H, EHD3:p.E44K,         EIF2C1:p.R139Q, ELF3:p.F305fs, ELMOD2:p.T141M, EMR2:p.S75L,         ENAM:p.R373H, ENOX2:p.R356W, ENTPD7:p.E327K, EPG5:p.D369N,         EPHB2:p.R392H, ERCC6:p.V780I, ERCC6L:p.R505Q, ERRFI1:p.A421T,         ESCO1:p.R300Q, ETV6:p.R369W, F8:p.S2269Y, FAM123B:p.F173fs,         FAM135B:p.R884H, FAM169B:p.K165N, FAM170A:p.E56K,         FAM171B:p.D459N, FAM181A:p.R109H, FAM5B:p.R402C, FBXO11:p.A432V,         FBXW7:p.R689W, FBXW7:p.S582L, FBXW7:p.R14Q, FGF14:p.A236V,         FHDC1:p.R254W, FHOD3:p.A225T, FHOD3:p.E813K, FMO3:p.F510L,         FNDC1:p.R652H, FOXK1:p.R354W, FOXN3:p.P96fs,         FPGT-TNNI3K:p.R455H, FZD3:p.D367N, GABRA4:p.R460Q,         GABRA5:p.S126N, GABRB3:p.D500N, GALNTL5:p.R262I, GJA1:p.R362Q,         GLRA3:p.L454I, GLRA3:p.F132L, GOLGA4:p.Q1536H, GP2:p.S41L,         GPC6:p.A214T, GPLD1:p.R717Q, GPR125:p.R113Q, GPR156:p.F754L,         GPR158:p.D566N, GPR21:p.R216H, GPR61:p.A62T, GPR98:p.R4142W,         GPRC5A:p.V30I, GRAP2:p.E69D, GRIA1:p.R218C, GRIA2:p.R845Q,         GRM7:p.R679Q, GTF3A:p.K306N, HAO1:p.R172C, HARS2:p.R168H,         HBB:p.F42L, HCN4:p.R525H, HDAC5:p.A1044T, HGF:p.S467Y,         HIPK4:p.R280H, HLA-DMA:p.E84K, HMG20A:p.E248D, HPS3:p.S468L,         HRSP12:p.R120Q, HS3ST1:p.E287K, HTR3B:p.R236C, HTR5A:p.R152C,         HTT:p.D1548N, HYDIN:p.R1187C, HYDIN:p.R939Q, HYDIN:p.R451Q,         HYOU1:p.R158C, IFT172:p.A944V, IGJ:p.R77Q, IL17RA:p.Q803fs,         IL1RAPL2:p.T647M, IL3:p.A90T, IL5RA:p.L47I, INPP5D:p.R523Q,         INPP5K:p.R263C, IRAK3:p.R267Q, IREB2:p.R419Q, ITGA4:p.T673M,         ITGA4:p.F900L, ITIH5:p.A912T, ITK:p.E196K, JAG1:p.A462T,         JAK1:p.V310I, KAL1:p.V303L KBTBD8:p.V549I, KCNA3:p.A415V,         KCND3:p.S438L, KCNMB4:p.F209L, KCTD20:p.L314fs, KDELC1:p.L447I,         KIAA0528:p.R181Q, KIAA0556:p.R1082W, KIAA1109:p.S4937Y,         KIAA1804:p.V474M, KIAA1804:p.R477W, KLF16B:p.R145Q,         KIF26B:p.A1114V, KPNA4:p.R29Q, KRAS:p.K117N, KRAS:p.Q61L,         KRAS:p.Q61K, KRT6B:p.L197P, L1CAM:p.T186M, LALBA:p.A41 T,         LAMA4:p.A558V, LBX1:p.R176W, LPAR4:p.R145Q, LRP1B:p.K2623N,         LRP2:p.R3043C, LRP2:p.S737L, LRRC18:p.R218W, LRRC3J:p.K23T,         LRRC7:p.R1389H, LZTS2:p.P100fs, MACF1:p.S292L, MACF1:p.F722L,         MAEL:p.R345C, MAGEE1:p.V380M, MAGI1:p.R1198C, MAP1B:p.E2046D,         MAP2:p.K530N, M4AP2K4:p.R287H, MAP3K4:p.R275Q, M4AP7D2:p.R487C,         MALPK8IP1:p.L217fs, MBOAT2:p.R43Q, MCF2L2:p.R926Q,         MECOM:p.R969C, METTL16:p.R200Q, METTL21A:p.R174Q, METTL6:p.F56L,         MFF:p.R162C, MFSD5:p.R280Q, MIA3:p.Q356H, MMAA:p.R326C,         MORC1:p.D113Y, MORC2:p.R740H, MPDZ:p.L804I, MR1:p.S46L,         MRPL47:p.L234I, MS4A8B:p.S3L, MSH4:p.K464N, MSH6:p.T1085fs,         MSH6:p.R1095H, MUC16:p.R8606H, MYH13:p.D311N, MYH7:p.R1689C,         MYO1D:p.E246K, MYO3A:p.N525H, MYO6:p.D1180N, MYO9A:p.R2179Q,         MYO9A:p.R167Q, MYOZ2:p.E251K, MYT1:p.E226K, NAA25:p.S807Y,         NCAM1:p.R474W, NCOA4:p.R562Q, NEB:p.D5434N, NEB:p.L1591I,         NEB:p.E1214K, NEDD9:p.A798T, NEDD9:p.A316T, NEK1:p.R608C,         NFASC:p.V256I, NINL:p.R1366C, NLRC4:p.D593N, NLRC4:p.E409K,         NLRP4:p.V229I, NLRP5:p.R392H, NME9:p.E75K, NOLC1:p.T428M,         NPC1:p.E451K, NPSR1:p.R235Q, NRAS:p.Q61L, NRAS:p.G13R,         NRAS:p.G12D, NRG2:p.T246M, NTN4:p.E59K, NUB1:p.R373Q,         NUDT15:p.S83 Y, NUF2:p.S340L, NUP88:p.A302V, ODZ1:p.R2556W,         OGDHL:p.A427T, OGFRL1:p.E427K, OLFM4:p.K132N, OPRM1:p.R353H,         OR10A3:p.S93Y, OR2M3:p.R235H, OR52W1:p.R133C, OR5AU1:p.R312H,         OR5B17:p.R163H, OR8S1:p.A99V, OSTN:p.R115Q, OTOL1:p.V431I,         OTUD3:p.R277I, PAN3:p.S580N, PANK3:p.R260I, PAX3:p.T424M,         PCBP1:p.L102Q, PCDH10:p.V477M, PCDH15:p.R1552I, PCDHAC2:p.A519T,         PCDHAC2:p.E190K, PCDHAC2:p.A266T, PCDHAC2:p.A156V,         PCDHAC2:p.E271K, PCDHAC2:p.A736V, PCDHB5:p.D51Y, PCDHB8:p.D235N,         PCDHGC5:p.S289L, PCDHGC5:p.V662M, PCNXL2:p.R135Q,         PCOLCE2:p.A348V, PCOLCE2:p.R87H, PDE4B:p.S417L, PGAM1:p.R240H,         PHF3:p.R1410I, PIAS2:p.S519L, PIGR:p.A580T, PIK3CA:p.D350G,         PIK3CA:p.E545A, PIK3CA:p.E545G, PIK3CA:p.Q546K, PIP4K2C:p.R204H,         PKHD1L:p.F1856L, PLA2G4A:p.E443K, PLCG2:p.E544K, PLCG2:p.D973N,         PLEKHA6:p.V328fs, PLEKHG4B:p.E384K, PLK1:p.D233G,         PLOD3:p.R297fs, PLSCR3:p.E77K, PLXNC1:p.S462L, PLXNC1:p.R819C,         POLA1:p.E603D, POLE:p.S459F, POLE:p.V411L, POLQ:p.R860Q,         PPP2R2B:p.P326L, PPP2R5C:p.S259Y, PRAMEF4:p.R248H,         PREX1:p.V731I, PRKAA2:p.R407Q, PRKAR2B:p.S309L, PRKCI:p.R480C,         PRKRA:p.K122N, PSG8:p.R397C, PSG8:p.R320C, PSMD12:p.R201Q,         PTPDC1:p.R430W, PTPN12:p.R765Q, PTPN13:p.S887L, PTPRD:p.L053I,         PTPRU:p.D1434N, PXDN:p.P856fs, PXDNL:p.T1312M, QRSL1:p.S226L,         RAB7L1:p.R79W, RALGAPA1:p.R398C, RANBP2:p.R1231C, RBBP7:p.E313K,         RBBP7:p.E274K, RBFOX2:p.A340T, RBMXL1:p.R331Q, RHOBTB1:p.T464M,         RIMS2:p.R599Q, RIN3:p.S708L, RLBP1:p.D281N, RLBP1:p.A72V,         RNASET2:p.A127V, RNF113B:p.A172V, RNF150:p.R236Q,         RNF150:p.S208L, RNF43:p.S216L, ROR2:p.D672N, RPL6:p.F193C,         RPS6KA5:p.E166K, RSPO2:p.R28C, RUVBL1:p.E431K, RUVBL1:p.R117C,         RWDD2B:p.R254H, RXFP3:p.R13C, RYR3:p.R2705Q, SAGE1:p.R229C,         SCFD2:p.R545W, SCML4:p.R194Q, SCN10A:p.T1570M, SCN11A:p.A1688T,         SCN11A:p.V1289I, SCN11A:p.V566I, SCUBE2:p.V342M, SEMA3A:p.D81N,         SEMA4D:p.R252Q, SEPHS1:p.R371Q, SEZ6L:p.S207L, SFPQ:p.R611Q,         SFSWAP:p.S617Y, SGCG:p.A220V, SGCZ:p.141M, SH3TC2:p.R89C,         SIGLEC11:p.S363F, SIPA1L1:p.R1063Q, SIPA1L1:p.S1227Y,         SLC12A1:p.S292L, SLC22A15:p.S201L, SLC24A2:p.A134V,         SLC25A40:p.R96Q, SLC2A7:p.A65T, SLC30A9:p.R194H,         SLC33A1:p.S542L, SLC35F3:p.A280T, SLC39A7:p.R382C,         SLC43A1:p.P133L, SLC43A3:p.R216H, SLC44A5:p.R185H,         SLC6A2:p.A562T, SLC8A1:p.R431H, SLFN12L:p.F232fs,         SLITRK1:p.R52H, SLITRK3:p.S298L, SMAD2:p.R321Q, SMARCA4:p.R38 Q,         SOCS5:p.S464L, SORBS1:p.V1156M, SORBS1:p.F570L, SORCS2:p.R320W,         SOX6:p.R719W, SPATA22:p.S150L, SPEG:p.A944V, SPTB:p.R86C,         SPTBN4:p.A1993V, STIM2:p.R572Q, STT3B:p.D583Y, SULT1C4:p.R85Q,         SUN3:p.E128K, SUPT6H:p.A957T, SYNE1:p.I1249L, SYNE1:p.R170W,         SYNE2:p.K3103N, SYNGR4:p.R169Q, SYT7:p.T349M, TANK:p.S380L,         TAS1R2:p.R270C, TAS2R:p.F183L, TCF7L2:p.R488C, TDRD10:p.S322L,         TECTB:p.L29I, TEKT5:p.R401H, TGFBR1:p.S241L, THAP5:p.S287Y,         THSD7B:p.R90H, TLL1:p.T153M, TLL2:p.S872L, TM9SF2:p.R91H,         TMCC3:p.R110H, TMEM132A:p.R481C, TMEM132D:p.R578W,         TMEM55A:p.R189Q, TMEM74:p.R125Q, TMPRSS11A:p.S288L,         TNIP2:p.A139T, TOP2B:p.R656H, TOX:p.S354L, TP53:p.G244D,         TP53:p.R175C, TPO:p.A826T, TPR:p.S2155L, TPTE2:p.R258Q,         TPTE:p.S423L, TRAK1:p.D627N, TRAPPC11:p.R568Q, TRIM23:p.R396Q,         TRIM44:p.D331N, TRIO:p.R661W, TRPA1:p.K54N, TRPC5:p.S490L,         TRPM6:p.R995H, TRPM7:p.R1862C, TRPM7:p.R843Q, TRPS1:p.R1125W,         TRPV5:p.R492H, TRRAP:p.R3515W, TSHZ1:p.R881M, TTC21A:p.S270Y,         TTN:p.R22795C, TTN:p.R3193Q, TTN:p.R328H, TUBA3D:p.R243Q,         TUFT1:p.A340T, TXNDC15:p.R343Q, UBE2NL:p.R86I, UBIAD1:p.A97T,         UGT2A1:p.N97fs, USH2A:p.F2369L, USP11:p.A286T, USP25:p.R119Q,         USP26:p.R861Q, USP29:p.F81L, USP31:p.D391N, USP40:p.S851L,         UTP14A:p.V148I, VAV3:p.E685K, VCAN:p.R1125H, VPS13C:p.D1359Y,         WBSCR17:p.R228C, WDR3:p.E841K, WDR52:p.A157T, XKR6:p.R268Q,         XPOT:p.R541W, YTHDC1:p.R267Q, YTHDC2:p.E634K, ZBBX:p.R596I,         ZBTB24:p.L607I, ZC3H13:p.R103Q, ZCWPW2:p.D144N, ZEB2:p.R156H,         ZFHX4:p.E237D, ZFP14:p.R386C, ZFP28:p.R525I, ZFP2:p.R150I,         ZFP3:p.R273I, ZFP90:p.R330Q, ZHX2:p.V790I, ZIC4:p.S305L,         ZIM3:p.D352N, ZKSCAN4:p.R319Q, ZMYM4:p.R1446Q, ZNF117:p.R185I,         ZNF167:p.R683I, ZNF180:p.R401I, ZNF19:p.R349I, ZNF205:p.R384C,         ZNF236:p.S1480L, ZNF248:p.R568I, ZNF259:p.R174I, ZNF266:p.R512Q,         ZNF266:p.R344Q, ZNF280B:p.E363K, ZNF283:p.R392Q, ZNF32:p.S62L,         ZNF345:p.R82Q, ZNF345:p.R334I, ZNF350:p.R310Q, ZNF434:p.R306C,         ZNF439:p.E239D, ZNF439:p.R262I, ZNF443:p.R301I, ZNF445:p.L682M,         ZNF470:p.R641I, ZNF471:p.R282I, ZNF484:p.R138C, ZNF528:p.R279Q,         ZNF563:p.K26N, ZNF573:p.R350I, ZNF583:p.R344I, ZNF585A:p.E638K,         ZNF585A:p.E491D, ZNF625:p.R235Q, ZNF652:p.K327N, ZNF677:p.R451I,         ZNF678:p.R368I, ZNF699:p.R41I, ZNF70:p.R244L ZNF770:p.S441P,         ZNF774:p.R423Q, ZNF782:p.K247T, ZNF7:p.R337I, and         ZNF831:p.E949D.

62. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from DLBCL, and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         EZH2:p.Y641F, MYD88:p.L273P, BCL2:p.G33R, CARD11:p.E626K,         ADCY2:p.A87V, BCL2:p.N172S, BCL2:p.H20Q, BRAF:p.K601E,         BTG1:p.L31F, CACNA1E:p.R1458C, CARD11:p.E93D, CD79B:p.Y197D,         CD79B:p.Y197H, CREBBP:p.R1446H, GRID1:p.E622K, HIST1H1C:p.A65V,         HIST1H1E:p.G133A, HIST1H3B:p.A48S, KRAS:p.G13D, MYD88:p.S251N,         PABPC1:p.R94C, PIM1:p.L164F, PIM1:p.L184F, POU2F2:p.T239A,         POU2F2:p.T239S, RELN:p.R2971Q, SLC25A48:p.A67T, STAT6:p.D468H,         TNF:p.L47F, and TRAF7:p.R11H.

63. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from KICH; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         ACR:p.W279C, AGRN:p.1284_1285VT>A, C7orf25:p.R384fs,         CAMSAP1:p.T466fs, CBWD6:p.E102fs, DOCK8:p.L1111fs, EBPL:p.Q196P,         EBPL:p.L89V, GFM1:p.A17fs, GOLGA6L6:p.D570E, ITGA5:p.A48D,         LUZP2:p.S154fs, MTMR9:p.K193fs, MUC16:p.P10452fs, MUC4:p.S2832P,         ODF2L:p.K407fs, RHBDD3:p.G34fs, RILPL1:p.S358R,         TAS2R30:p.L236fs, TRRAP:p.A973S, UBR5:p.K2120fs, URGCP:p.G639fs,         ZNF98:p.A222T, and ZSWIM6:p.Q610fs.

64. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from KIRP; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         FAM18B2:p.C51Y, ZNF598:p.E25G, NEFH:p.E645K, EEF1B2:p.S43G,         NEFH:p.AKSPEKEE652del, OBP2B:p.K61N, SKI:p.A62G,         C14orf126:p.R6W, KRT8:p.S59A, ACSBG2:p.I250M, ASIC2:p.R46L,         CSGALNACT2:p.L362F, FRG1B:p.A50P, IDUA:p.H33Q, KRTAP4-5:p.S74C,         SCAF11:p.E926fs, SYN2:p.A34del, ZNF814:p.R322K, BMS1:p.E878D,         JMY:p.P822T, KIF1A:p.E917D, KRTAP4-7:p.S57P, LAMA5:p.L2223R,         LRP1:p.P1058T, MED16:p.H449Q, MUC2:p.T1488P, MUC5B:p.D682G,         NACA2:p.R75K, NEFH:p.665_666insEE, OR2L8:p.S201fs,         RGPD5:p.P1760A, RRN3:p.P1 S, RRN3:p.R9C, STAG3L2:p.L81fs,         ZNF814:p.G320E, ACP6:p.V29G, AHNAK2:p.S2166F, AHNAK2:p.P1215S,         AP1G1:p.1782fs, AQP2:p.N68T, BAIAP2L2:p.V396M, BMP6:p.Q118L,         BST1:p.G36A, CDR1:p.V31A, CLDN7:p.S172A, CLIP 1:p.S1018fs,         COL18A1:p.G884fs, CROCC:p.A355P, CTAGE15P:p.A364V,         CUBN:p.I2816M, DMRT2:p.T106S, DPY19L1:p.V249L, DSPP:p.D1047N,         EBPL:p.L189V, EIF4G1:p.E465del, EXOSC2:p.R11P, FAM216A:p.P36S,         FCGR2A:p.V222G, FMOD:p.S331R, FOLR2:p.Q112R, FRG1B:p.L20P,         GAGE2B:p.9_10insY, GDPD5:p.G593fs, GIMAP8:p.A544S,         GLUD2:p.R300G, GLUD2:p.S496R, GPR135:p.Q5P, HOXD8:p.Q67H,         IER5:p.R194G, IL25:p.C168fs, JSRP1:p.V92A, KRAS:p.G12D,         KRTAP1-1:p.Y86C, KRTAP4-11:p.L161V, LTBP1:p.L163P,         MAML2:p.Q591K, MAPK7:p.A501D, MEF2A:p.P99S, MET:p.H1094Y,         MET:p.M1250T, MST1:p.N435fs, MUC2:p.T1582R, MUC2:p.T1722I,         MUC4:p.A4222T, MUC4:p.T2335M, MUC4:p.P1138L, MUC5B:p.S1098A,         MUC5B:p.S3431N, MYH7:p.A1487T, NBPF10:p.R39fs, NBPF10:p.Y638S,         NEFH:p.654_654S>SPEKAKS, PARG:p.A584T, PBX2:p.Y262F,         PIP4K2A:p.R219K, RLIM:p.S471P, RUNX2:p.Q71E, SGK223:p.R63S,         SMARCB1:p.L365fs, SRCAP:p.Q1875fs, TBC1D2B:p.R920Q,         TCF7L2:p.R482fs, TMEM131:p.K640fs, TMEM60:p.K77fs, TPPP:p.R30K,         TRPV3:p.A218E, TTBK2:p.C83W, UBXN11:p.S510G, UGT1 A1:p.T4A,         UTS2R:p.A289E, YBX1:p.P250L, ZNF514:p.V81G, ZNF516:p.A256D,         ZNF681:p.K405Q, ZNF814:p.D404E, ZNF814:p.P323H, ZXDB:p.G206R.

65. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from LIHC and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         TP53:p.R249S, CTNNB1:p.D32V, CTNNB1:p.D32G, CTNNB1:p.S33P,         CTNNB1:p.K335I, CTNNB1:p.H36P, EEF1A1:p.T432L, GNAS:p.R844C,         OR2T4:p.V137L, TP53:p.H193R, ATXN1:p.Q217H, CSMD3:p.F2383fs,         CTNNB1:p.D32N, CTNNB1:p.S33C, CTNNB1:p.G34V, CTNNB1:p.S45P,         CTNNB1:p.N387K, DHRS4:p.I218T, DNM2:p.E378D, F5:p.Q426L,         GALNTL5:p.A45T, GPX1:p.P77R, GRM8:p.R852C, IDH1:p.R132C,         KIF26B:p.A2033T, KRT8:p.S59A, LOC100132247:p.T532P,         NEB:p.D3854H, PIK3CA:p.H1047R, SOLH:p.R714H, TP53:p.R158H,         TP53:p.V157F, and ZNF638:p.D400N.

66. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from MM: and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         NRAS:p.Q61R, KRAS:p.Q61H, KRAS:p.G13D, NRAS:p.Q61K,         BRAF:p.V600E, NRAS:p.Q61H, NRAS:p.G13R, ZNF717:p.W315C,         ATP13A4:p.V431G, DNAJC12:p.R135K, IRF4:p.K123R, KRAS:p.A146T,         KRAS:p.Q61R, KRAS:p.G12A, KRAS:p.G12D, ZNF717:p.N594I,         ACTG1:p.A22P, ARL61P1:p.M75L, BEND2:p.E630K, BRAF:p.G469A,         CDHR1:p.R218G, DIS3:p.R780K, DMXL2:p.D2412E, DNAJC10:p.I80K,         EGR1:p.Q9H, FGFR3:p.*807S, IDH1:p.R132C, IL6ST:p.P216H,         INTS12:p.M1V, KRAS:p.K117N, KRAS:p.A59G, KRAS:p.G12R,         MAX:p.R36W, MLL5:p.G492E, NBPF1:p.E810K, NRAS:p.Q61L,         NRAS:p.G12D, ODF2L:p.E294K, PADI2:p.T114P, PNLIP:p.T37M,         PRDM1:p.S588C, PTPN11:p.E76K, PTPN14:p.E286K, RBM6:p.V675G,         SCN10A:p.R142H, SRGAP1:p.T61M, SUSD1:p.T168P, TAS2R16:p.V231I,         TINAG:p.E403K, TRIP12:p.L1775P, and ZNF717:p.C844S.

67. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from PRAD; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         HSD17B7P2:p.N175S, RGPD5:p.P1760A, FRG1B:p.L52S, EEF1B2:p.S43G,         FRG1B:p.I10T, FRG1B:p.A53T, LRRC37A2:p.T102S, NBPF10:p.E3455K,         PTH2:p.L22V, CYP2D7P1:p.S32A, FAM47C:p.N648D, MAP3K9:p.E38del,         MUC4:p.H4205Q, CHEK2:p.K373E, FRG1B:p.A11T, FRG1B:p.A50P,         HLA-J:p.R124W, KRTAP1-5:p.I88T, KRTAP4-9:p.D18V, NPIP:p.A271V,         PDGFRA:p.R483fs, ZNF780A:p.Q600H, ZNF845:p.R925H, ZNF91:p.R333H,         ARFGAP3:p.N299fs, BTN2A3P:p.P3S, FNBP4:p.TT58del, HLA-A:p.Q78R,         LOC554223:p.RAPWMEQ147del, PODXL:p.28_30PSP>P, POLI:p.D17del,         SPOP:p.F133L, SYN2:p.A34del, TMEM52:p.23_26LLPL>L, UBC:p.L149R,         ZNF208:p.I647S, ZNF799:p.E589G, ZNF814:p.D404E, ASTN2:p.L221del,         B4GALNT1:p.G88fs, C16orf74:p.S21del, CCDC15:p.H458P,         CD209:p.R129W, CNTNAP1:p.S1029I, DBR1:p.541_542DD>D,         FAM22F:p.S691del, FRG1B:p.D32V, FRG1B:p.I34T, FRG1B:p.N55D,         FRG1B:p.I59V, FRG1B:p.S71N, KIF25:p.W3R, KRTAP4-11:p.L161V,         KRTAP4-11:p.M93V, KRTAP4-11:p.R51K, KRTAP4-6:p.S153Y,         LILRB5:p.S598P, LMOD2:p.E24del, LOC645752:p.L40P, LRP1:p.P1058T,         LRRIQ3:p.K244fs, LURAP1L:p.55_56insGGG, MLLT10:p.V463E,         MYOCD:p.Q310del, NBPF10:p.N1369D, OTUD4:p.T909I, PARG:p.A584T,         PEX1:p.I370fs, POTEC:p.K507E, POTEC:p.R477Q, POU4F2:p.68_69insG,         PRG4:p.T417P, SDHAP2:p.R31C, SPOP:p.F133C, SPOP:p.W131G,         TIMD4:p.T152del, TMEM121:p.P299del, TP53:p.G245S, UBC:p.R73L,         UBC:p.I191T, WASH3P:p.G175S, ZMIZ1:p.D1048fs, ZNF709:p.T413I,         ACADS:p.R330H, ADAMTS7:p.K1357fs, AFF2:p.R597H, AGAP6:p.S127I,         AK302238:p.A44T, AK302879:p.Q191R, ALDH1A2:p.R85C,         ANAPC1:p.T537A, ANKRD36C:p.H438R, AP4B1:p.R276W, ARFGAP2:p.S38N,         BBS9:p.F268fs, BC139719:p.L133R, BRAF:p.G469A,         C22orf43:p.D171del, CANT1:p.K131R, CHD3:p.E35del,         CLEC4A:p.R209H, CNOT3:p.E20K, CNPY3:p.17_18LL>L,         CNTNAP3B:p.S317T, CNTNAP3B:p.M1247I, CTNNB1:p.T41A,         DDX10:p.D788del, DLC1:p.S741T, DPY19L2:p.M210V, EDC4:p.S617del,         EFCAB6:p.R379K, ERC2:p.927_928HH>H, FAM111B:p.S269fs, FEM         1A:p.L620M, FHOD3:p.A632fs, FLJ43860:p.L850fs, FMN2:p.G59del,         FNBP4:p.914_915PP>P, FRG1:p.E86del, FRG1B:p.K13N, FRG1B:p.P42Q,         GABRB1:p.R416C, GABRR2:p.A368V, GAGE2B:p.9_10insY,         GOLGA8DP:p.N84H, GOT2:p.R355W, GPATCH4:p.K210fs,         HDGFL1:p.188_189insA, HLA-DQB2:p.G250S, HLA-DQB2:p.R247H,         IDH1:p.R132H, 1L27:p.E176del, IRF2BPL:p.123_125QQQ>Q,         KANK3:p.DGDS489del, KIAA1462:p.858_859SS>S, KRTAP4-11:p.S48R,         KRTAP4-7:p.S57P, KRTAP4-8:p.C95S, LPHN3:p.R826H, LRP10:p.L11del,         LRP5:p.S1609P, LRRC16B:p.R787W, MAS1L:p.R324G, MECOM:p.R915Q,         MED12:p.L1224F, MED12L:p.Q2115del, MESP2:p.GQGQGQGQ195del,         MGAT4C:p.T345M, MLEC:p.E238del, MSLNL:p.T68P, MUC7:p.S173P,         MYC:p.Q37del, NBPF10:p.N440D, NLRP6:p.E611del, NOX3:p.C404fs,         OR1M1:p.V69I, OR7E24:p.L7fs, OTUD4:p.A153del, PANK2:p.T417fs,         PCLO:p.S496P, PCNT:p.S162G, PCSK9:p.23_24insL,         PHOSPHO1:p.S32del, POU4F1:p.H108del, PRAMEF8:p.R319H,         PRDM7:p.M387L, PRG4:p.T597P, PTPRD:p.R1323C, PTPRF:p.R1174Q,         ROBO3:p.RS1367del, ROCK 1:p.T518S, RPTN:p.G296S,         RTL1:p.152_152E>EE, SIRPA:p.V233I, SLC2A6:p.A230D,         SLC8A2:p.E710del, SMG7:p.E846fs, SNAPC4:p.S542del,         SP8:p.G165del, SPOP:p.F133I, SPOP:p.F33V, SPOP:p.F102C,         SPOP:p.F102V, SRSF11:p.G17fs, SRSF4:p.K396del, SSPO:p.S4198fs,         STAG3L2:p.L81fs, STK19:p.R18fs, TBC1D2B:p.R920Q,         TBC1D9:p.P1233T, TCHH:p.P1158R, TCOF1:p.K1366del,         TNRC18:p.2664_2665SS>S, TP53:p.R248Q, TP53:p.R175H,         TP53:p.C141G, TSPAN4:p.L92V, UBXN11:p.GPGPGPSP504del,         UTP3:p.E81del, WASH3P:p.L187V, ZAN:p.P717L, ZAN:p.L878P,         ZFP90:p.R591fs, ZNF761:p.H373R, and ZNF91:p.H305R.

68. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from STAD; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         RNF43:p.G659fs, BZRAP1:p.P1416fs, XYLT2:p.Y526fs,         LARP4B:p.T163fs, PGM5:p.I98V, ZBTB20:p.P692fs, ARID1A:p.G1848fs,         FHOD3:p.P334fs, KIAA0182:p.T120fs, ATP6V1B1:p.Y383fs,         PIK3CA:p.H1047R, FRMD4A:p.P1005fs, PIK3CA:p.E545K,         CDC14A:p.N123fs, KRAS:p.G13D, MLL2:p.T172fs, BCORL1:p.S1679fs,         PLEKHA6:p.V328fs, C9orf131:p.P342fs, CD4:p.Q164fs,         FBXW7:p.R465C, GNG12:p.T68fs, IRS4:p.G591fs, JARID2:p.V422fs,         KIAA0195:p.I902fs, MBD6:p.P732fs, MVK:p.P138fs, PAMR1:p.G101fs,         WNT16:p.W165fs, ZNF43:p.N251fs, ABCA6:p.L306fs, ADAM28:p.K73fs,         AOC3:p.L79fs, ATP2A:p.R819fs, B2M:p.L13fs, C6orf89:p.P58fs,         CNTLN:p.K1305fs, CR2:p.V206fs, DYRK4:p.K468fs, ERBB3:p.V104M,         GLI1:p.W272fs, KRAS:p.G12D, MLL2:p.T72fs, MSH6:p.T1085fs,         NLK:p.C190fs, OR5M3:p.T89fs, PAX6:p.P375fs, PTEN:p.L265fs,         RABGAP1:p.K928fs, RAD51 AP2:p.T316fs, SVIL:p.G1862fs,         TP53:p.R273H, WNK4:p.G606fs, ARID1A:p.P2139fs, AXIN2:p.G665fs,         C13orf33:p.R67fs, C1QTNF5:p.P308fs, CELSR1:p.G614fs,         CRYGD:p.G159fs, DCHS1:p.R235fs, DDC:p.I433fs, EDNRB:p.Y383fs,         EPHA2:p.P460fs, FOXN3:p.P96fs, HDAC4:p.P901fs, INF2:p.S527fs,         KIRREL2:p.V649fs, KLF3:p.I104fs, KLHL14:p.P231fs,         MAP7D3:p.Q308fs, OTX2:p.R44fs, PAFAH1B1:p.K302fs,         PLAGL2:p.P10fs, POLM:p.P97fs, PRPF40B:p.I31fs, RALGAPB:p.T379fs,         SBNO1:p.N1139fs, SERPINI1:p.L81 fs, SH3KBP1:p.L574fs,         SLC2A7:p.H686fs, SLC27A3:p.P643fs, TBX4:p.S370fs, TP53:p.R273C,         TP53:p.R175H, TRAM1L1:p.R345fs, WBP1:p.P138fs, ABCC4:p.L883fs,         AKAP13:p.K2785fs, ALDH3A1:p.P562fs, ALPK2:p.L356fs,         ARFGEF1:p.P1552fs, ARID1A:p.G1848fs, AVPR1A:p.F351fs,         BAX:p.M38fs, C14orf43:p.P33fs, C1QTNF5:p.G194fs,         C7orf50:p.L179fs, CDC25C:p.K322fs, CETN3:p.K63fs, CHD3:p.P597fs,         CTCF:p.K202fs, CTSC:p.F05fs, DDX17:p.G163fs, DLGAP3:p.G377fs,         EBF3:p.G255fs, FHDC1:p.F100fs, FILIP1L:p.K749fs, FLNB:p.W529fs,         GBP7:p.G431fs, GCC2:p.E700fs, GPR161:p.G517fs, IWS1:p.S802fs,         KIAA0240:p.K895fs, KIAA1967:p.P415fs, LRRC43:p.D558fs,         MACF1:p.R707fs, MBD6:p.G780fs, MLL3:p.F4496fs, MPRIP:p.A35 fs,         MUC6:p.2129_2130SS>S, NOX5:p.P467fs, OPTN:p.P24fs,         OR4K5:p.F177fs, PIK3CA:p.N345K, PIK3CA:p.E542K,         PLXNA1:p.P1016fs, PNPLA7:p.P1199fs, PODN:p.I301fs,         PPP2R3B:p.T389fs, PRSS36:p.L680fs, RGL2:p.G203fs, RHOQ:p.V190fs,         RNF111:p.R771fs, RTN2:p.P313fs, SALL4:p.V995fs, SBF1:p.P1076fs,         SETDB2:p.R715fs, SNAPC2:p.T292fs, SPG20:p.F232fs,         SRCAP:p.P1876fs, STAT2:p.P489fs, TCHP:p.E172fs, TP53:p.R282W,         TP53:p.R248Q, USP21:p.K474fs, WDR7:p.G262fs, ZBTB7C:p.E157fs,         ZFC3H1:p.K385fs, ZNF124:p.T339fs, ZNF626:p.K115fs,         ADNP2:p.S322fs, AGAP1:p.G127fs, ALDH2:p.L286fs,         ARHGAP5:p.D890fs, ARHGEF17:p.A615fs, ARID1A:p.Y1324fs, ART         1:p.I243fs, ASCL4:p.D35fs, ATXN2L:p.G998fs, B3GNT5:p.F30fs,         BCKDHA:p.H37fs, BCL9L:p.P1127fs, BEND3:p.D265fs, BNC2:p.S575R,         BRD3:p.P24fs, C12orf51:p.P4235fs, C1R:p.P216fs,         C7orf49:p.G130fs, CA2:p.I145fs, CABP5:p.R145fs, CASD1:p.F781fs,         CASP8:p.R471fs, CCDC153:p.P200fs, CD93:p.D280fs, CROT:p.L32fs,         CSF3R:p.P468fs, CTCF:p.K202fs, ERBB2:p.S310F, FAM46D:p.S69R,         FBN3:p.G601fs, FBXO21:p.F144fs, GAS6:p.G150fs, GLYR1:p.G380fs,         GXYLT1:p.L223fs, HAUS6:p.S530fs, IGF2R:p.T1314fs, ITGB1:p.L378I,         KDM3B:p.P1316fs, KIF13A:p.K1115fs, KLF3:p.S224fs,         LARP1:p.A223fs, LRP1:p.G1488fs, LRP1:p.G1488fs, MAGEE2:p.Q45fs,         MAMSTR:p.P162fs, MAPK15:p.Q511fs, MLL2:p.P647fs, MOCS2:p.P22fs,         MTG1:p.L105fs, MTG1:p.H327fs, MTIF2:p.N109fs, NID2:p.R1035fs,         PAX2:p.P395fs, PCCA:p.R230H, PDZD2:p.R01fs, PFKP:p.M593fs,         PIK3CA:p.R88Q, PLA2G1B:p.L53fs, PLAU:p.R201fs, PMEPA1:p.P208fs,         POP1:p.K750fs, PTCH1:p.P1307fs, PTPRT:p.P1075fs, RDBP:p.P6fs,         RNMT:p.K392fs, ROBO2:p.P1080fs, RUNDC3B:p.L6fs, SDAD1:p.K275fs,         SLC10A6:p.G109fs, SNAPC1:p.D21 fs, SPATA5L1:p.C685fs,         SPTA1:p.K1732T, STAT5B:p.P367fs, SYT4:p.M1fs, TAF1L:p.K851fs,         TAP2:p.L75fs, TBL1XR1:p.N126fs, THEMIS:p.K406fs,         TMEM79:p.P161fs, TP53:p.C176F, TP53BP2:p.K69fs, TP53RK:p.L174fs,         UBQLN2:p.A523fs, UHRF1BP1:p.11330fs, VPRBP:p.K939fs,         VPS13B:p.T56fs, WASF3:p.P305fs, YLPM1:p.E1178fs,         ZC3H13:p.K1006fs, ZC3H18:p.P825fs, ZC3H4:p.E779Q,         ZNF48:p.P247fs, ZNF608:p.A465fs, ZNF878:p.S238fs,         ZSCAN18:p.P225fs, ABCB1:p.R527fs, ABCB6:p.G318fs,         ACACB:p.G255fs, ACP1:p.Q123fs, ACTL6A:p.L88fs,         ADAMTSL4:p.G778fs, AGBL5:p.I420fs, AHI1:p.K303fs,         AKAP9:p.M3743fs, AKD1:p.R1209fs, ANKRD40:p.D99E,         ARHGEF5:p.S1512fs, ARID1A:p.K1071fs, ARID3A:p.S557G,         ARPP21:p.I130fs, ASPN:p.F67fs, ASXL3:p.E873fs,         ATP6V1C2:p.R312fs, BEST3:p.P444fs, BRAF:p.P403fs,         BRMS1:p.G107fs, BTBD11:p.T451fs, BTBD11:p.A561V,         C11orf9:p.S261fs, C14orf102:p.R90fs, C14orf43:p.Q36fs,         C15orf52:p.G98fs, C19orf21:p.R262C, C19orf70:p.P50fs,         C20orf160:p.P46fs, C3:p.P890fs, CADPS2:p.N468fs, CASC3:p.S232F,         CASC3:p.P603L, CASC3:p.P645L, CASC3:p.S658L, CASKIN2:p.P727fs,         CBLL1:p.E138fs, CBLN3:p.P69fs, CCDC108:p.P164fs,         CCDC148:p.K420fs, CCDC153:p.P200fs, CCDC169-SOHLH2:p.K162R,         CCDC88A:p.K677fs, CD1E:p.F85V, CD3EAP:p.K218fs, CDH11:p.K357T,         CDH1:p.D254Y, CDH23:p.V403I, CFI:p.K37fs, CHPF2:p.D645fs,         CIC:p.R507fs, CIC:p.A1114fs, CIC:p.A1114fs, CLSTN1:p.T615M,         CNBD1:p.L396P, CNGA4:p.K510T, CNOT6:p.S248fs, CNTROB:p.R920fs,         COL9A1:p.P283fs, CPAMD8:p.P784fs, CR1L:p.L79fs, CRB1:p.F630V,         CSMD1:p.L3410V, CTNNA3:p.K856fs, CTNND1:p.I447fs, CTSD:p.P89fs,         CUX1:p.A439fs, CYP7B1:p.K332T, DAB21P:p.D994fs, DNAH11:p.T871fs,         DNAH8:p.K1688fs, DNAJC1:p.K193fs, DNM2:p.P791fs, DSTN:p.F101fs,         DYRK1B:p.Q545fs, EAF2:p.V109fs, EDNRB:p.A104V, EEA1:p.N570fs,         EFHA1:p.F290fs, EGR1:p.P332fs, EIF4G3:p.K563fs, ELK3:p.S173fs,         ENTPD2:p.G204fs, EOMES:p.G332fs, EPHA10:p.P868fs, EPHB6:p.G54fs,         EPHX1:p.P132fs, EPPK1:p.G2015fs, ERBB4:p.M1fs, ESF1:p.T99fs,         EXOSC8:p.L160fs, FAM113B:p.R5 fs, FAM116A:p.L44 fs,         FAM135B:p.S645R, FAM151A:p.P117fs, FAM193A:p.D428fs,         FAM193A:p.D428fs, FAM214B:p.A42fs, FAM40B:p.R740C,         FAM70B:p.S19L, FASTKD1:p.K3fs, FBXW7:p.R479Q, FBXW9:p.G298fs,         FER:p.L474fs, FERMT2:p.K152fs, FGGY:p.G138fs, FIGNL1:p.K309fs,         FLG:p.K159fs, FLNB:p.W529fs, FOLH1:p.S501fs, FYB:p.G324fs,         GABRD:p.Q412fs, GALNTL1:p.W317fs, GANAB:p.L23fs, GCDH:p.L389fs,         GIMAP7:p.V276fs, GIPC3:p.G227fs, GLI3:p.P033fs,         GLIPR1L2:p.G92fs, GNPNAT1:p.F54fs, GON4L:p.M134fs,         GPATCH4:p.K210fs, GRK4:p.K22fs, GTF3C1:p.S767fs,         GTF3C4:p.E562fs, H2AFY2:p.K144fs, HCFC1R1:p.P83fs,         HCRTR2:p.S9fs, HCRTR2:p.S9fs, HDLBP:p.G747fs, HECA:p.R333fs,         HIVEP3:p.H554fs, HIVEP3:p.P534fs, HLA-C:p.P209fs,         HOOK1:p.L361fs, HOXD8:p.P122fs, HTT:p.G697fs, IBTK:p.K1213fs,         IDE:p.K37fs, IFT172:p.A837T, INPPL1:p.A974fs, INPPL1:p.P1154fs,         INSM2:p.T533fs, INTS12:p.L14fs, INVS:p.R815fs, IPO11:p.S844fs,         IRX6:p.A425V, ISG20L2:p.P288fs, ITGB8:p.A7fs, JARID2:p.G394fs,         JHDM1D:p.R97fs, KBTBD6:p.G442fs, KCNC1:p.K455fs, KCNH2:p.G149A,         KCNJ10:p.P102fs, KCNMB2:p.N151K, KCTD21:p.T6M,         KIAA0586:p.A1592fs, KIAA1009:p.F406fs, KIAA1109:p.E1588fs,         KIAA2026:p.K690fs, KIF26B:p.S1065fs, KIF6:p.L204fs,         KIRREL:p.P335fs, KLC2:p.T568fs, KRAS:p.Q61H, KRAS:p.G12S,         MAN1C1:p.G431fs, MAP A:p.P2063fs, MAP2:p.K1472fs,         MAP3K12:p.R449del, MAP7D1:p.A80fs, MGST2:p.K102fs,         MKI67:p.T1664fs, MKL1:p.P307fs, MLL2:p.P2354fs, MLL2:p.L656fs,         MLL2:p.P647fs, MLL2:p.L1877fs, MMP3:p.I64fs, MPDZ:p.K1582fs,         MTUS2:p.R1005W, MUC16:p.A6156T, MYB:p.R481fs, MYEOV:p.L269fs,         MYH11:p.K1263del, MYO18A:p.P209fs, MYO7A:p.I539fs,         MYOCD:p.G226fs, NAA16:p.H514fs, NBEA:p.V2247fs, NCAPD3:p.Q909fs,         NCAPH:p.T466fs, NCOR2:p.P1308fs, NEFM:p.A213V, NEK8:p.V690fs,         NF1:p.T676fs, NHLRC1:p.F204fs, NKD1:p.P286fs, NPR3:p.Y138H,         NT5M:p.P206fs, NUFIP2:p.R224fs, NUP210:p.L135fs,         NYNRIN:p.G113fs, OBSCN:p.G997fs, OGDH:p.Y948fs, OR4C16:p.S135R,         OR51A7:p.L124R, OR7C1:p.C179fs, OSBP2:p.H627fs, OTOF:p.E1304K,         P2RX1:p.R20fs, PALB2:p.M296fs, PALB2:p.N280fs, PANK1:p.K400fs,         PAPD4:p.C225fs, PAPPA2:p.I1683fs, PARP15:p.K461fs,         PARP4:p.K847fs, PCDH10:p.N118fs, PCDH10:p.P225fs, PCGF3:p.H63fs,         PELI2:p.G197fs, PHACTR1:p.V251 fs, PHACTR2:p.S237fs,         PHACTR4:p.S354fs, PHKB:p.K642fs, PIAS3:p.H116fs, PIGO:p.P787fs,         PIGT:p.A346fs, PIK3R3:p.M341fs, PITPNM1:p.P295fs, PKN2:p.K76fs,         PLA2G15:p.W230fs, PLAG1:p.K184fs, PLEKHO1:p.T254fs,         PLOD3:p.R297fs, PLOD3:p.P296fs, PLXNA2:p.P464fs, POLQ:p.L1430fs,         PPARGC1B:p.P135fs, PPL:p.P454fs, PPM1H:p.P226fs,         PPP1R12C:p.P372fs, PREX2:p.R562fs, PRICKLE4:p.Q109fs,         PRKAR1B:p.P87fs, PRKCG:p.R345C, PRMT8:p.S28fs, PROX1:p.F592fs,         PRRG3:p.R163fs, PSD2:p.G256fs, PTCHD3:p.F588fs, PTPN4:p.N319fs,         PTPRC:p.Q895H, PWWP2B:p.S84fs, PYGO2:p.Q150fs, RABGAP1:p.K928fs,         RB1CC1:p.N1711fs, RBM6:p.R96fs, RHOA:p.Y42C, RIMS1:p.R71G,         RIMS2:p.V401fs, RING1:p.G171fs, RINT1:p.L107fs, RNF43:p.P116fs,         ROBO2:p.K1293fs, RPS6KA6:p.K109fs, RRS1:p.N45fs, RSF1:p.K386fs,         RUSC2:p.P486fs, RXFP3:p.A60V, SAFB:p.W798fs, SCARF1:p.R614Q,         SCLT1:p.K109fs, SERPINB12:p.Q168fs, SGK3:p.L61fs,         SGOL2:p.E407fs, SIGLEC1:p.P318fs, SIK1:p.Q678fs, SLC6A6:p.G98fs,         SLC25A17:p.F28fs, SLC26A7:p.1629fs, SLC32A1:p.V494I,         SLC4A3:p.L061fs, SLC7A10:p.P157fs, SLC9A2:p.T746fs,         SLITRK1:p.K45fs, SND1:p.H721fs, SOAT1:p.F64fs, SORBS2:p.E1158fs,         SOX7:p.L309fs, SPAG17:p.Q264fs, SPTY2D1:p.P485fs,         SRCIN1:p.P865fs, SREBF2:p.H763fs, SRRT:p.G102fs,         STAB1:p.P1120fs, STRADA:p.R333fs, STX2:p.K252fs, SV2A:p.E138fs,         SYCP2:p.M176fs, SYNJ2:p.P1111fs, TAS2R10:p.L196fs,         TBC1D22B:p.A75fs, TEAD2:p.P298fs, TFE3:p.G482fs, TGM6:p.T358fs,         TIMM44:p.K83fs, TIMP3:p.A199fs, TLR4:p.L498V, TMEM132D:p.P206fs,         TMEM41A:p.F156fs, TMEM41B:p.F230fs, TMTC4:p.R611C,         TNK2:p.P632fs, TOPBP1:p.I1381fs, TP53:p.E286K, TP53:p.P152fs,         TRIP11:p.K541fs, TRPA1:p.T673fs, TRPM8:p.H765fs, TTF1:p.K336fs,         TTI1:p.R707H, TTN:p.E15192D, U2AF2:p.L175fs, UBC:p.G684fs,         UBR4:p.P2802fs, UPF2:p.E1033D, UPK2:p.P49fs, USP13:p.I116fs,         USP15:p.K782fs, VASH1:p.G3fs, VEZF1:p.355_356insN,         VPS13A:p.F2883fs, WAPAL:p.R522fs, WDFY3:p.L842fs,         WDR59:p.N160fs, WDR5:p.N214fs, WDR60:p.Q412fs, WDTC1:p.M287fs,         WHSC1L1:p.K418fs, WNT1:p.W167fs, XIRP2:p.E1007D, YBX2:p.P226fs,         YIF1A:p.R131fs, ZBBX:p.E151del, ZBTB40:p.L262fs,         ZBTB7C:p.G342fs, ZBTB7C:p.D154fs, ZC3H18:p.T701fs, ZDHHC5:p.E651         del, ZDHHC7:p.P316fs, ZFHX3:p.R1893fs, ZFHX3:p.E763fs,         ZFHX4:p.L408fs, ZHX3:p.N249K, ZIM3:p.I384fs, ZKSCAN5:p.D13fs,         ZMYM4:p.K345fs, ZNF236:p.T1410M, ZNF23:p.F122fs,         ZNF334:p.K426fs, ZNF358:p.T130fs, ZNF701:p.L296fs,         ZNF711:p.L737fs, and ZNF831:p.A49fs.

69. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from TGCT; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         FAM18B2:p.C51Y, BTN2A3P:p.P3S, MUC2:p.G1715S, NBPF10:p.L44V,         SP8:p.G156S, DCP1B:p.Q252H, DEK:p.E41D, ERC1:p.K692R,         FAM104B:p.D75H, FRG1B:p.M49V, KRTAP10-10:p.V234M, LRRCC1:p.A6V,         NRAS:p.Q61R, PNPLA4:p.L223P, ANKLE1:p.C644fs, ANKLE1:p.C644fs,         KIT:p.D816H, KIT:p.D816Y, MUC2:p.T1597I, PSMD11:p.A5V,         RHPN2:p.V73M, RUNX2:p.Q71E, SP4:p.E7K, TUBA1C:p.L146F,         ZNF814:p.Y324H, ADAMTS17:p.N572T, ATRX:p.K1936R, BCL11B:p.E535D,         BMP2K:p.Q460H, BMP2K:p.H487Q, C12orf32:p.D60V, C22orf43:p.K19E,         CDC27:p.N571I, CDC27:p.P242S, DDX11:p.K208fs, EBPL:p.L189V,         EZH2:p.K510R, FAM86A:p.A141T, GAS2L2:p.D189A,         GRID2IP:p.LS754del, HGC6.3:p.E171G, KIT:p.D816V, KIT:p.N822Y,         KIT:p.N822K, KRAS:p.Q61R, KRAS:p.G12V, KRTAP1-1:p.I116V,         LRRC37BP1:p.Y166D, MEF2A:p.R127Q, MFF:p.S7F, MST1:p.R347W,         MUC4:p.S3048L, MUC6:p.H2000Q, MUC6:p.P1977H, NAT10:p.I393T,         OPLAH:p.A900D, PIEZO1:p.Q749E, PRAMEF4:p.F300V, RBM10:p.E184D,         SERINC2:p.T121P, SPIN2A:p.M150V, SRRM2:p.A2257S, SSBP3:p.K6R,         ZNF680:p.R501W, ABCC8:p.Y512C, ABCC9:p.L466P, ABCD1:p.H169Q,         ABL2:p.P19T, ACVR2B:p.R48C, AHDC1:p.P33fs, AHNAK2:p.L1640M,         ALPPL2:p.W31 S, AMMECR1:p.G77C, ANK3:p.D1322E,         ANKHD1-EIF4EBP3:p.G60S, ANKRD11:p.Y2015S, ANKRD11:p.K369R,         ANKRD50:p.V637M, APBB3:p.L450P, ARHGAP24:p.T35A,         ARID4B:p.G1076A, ARMC3:p.A514T, ARRB2:p.T99P, ATAD5:p.I305V,         ATXN3:p.305_306insQQQQQQQ, AVPR1B:p.G39R, AXDND1:p.E994Q,         BAI2:p.A231G, BEST3:p.P383L, BIRC6:p.V414L, BIRC8:p.A225M,         BRWD1:p.K1319R, BTN2A2:p.L15F, C12orf51:p.A2644T,         C12orf65:p.K143T, C16orf62:p.L244I, C1QBP:p.T225I,         C1orf167:p.S123G, C5orf25:p.Y4F, CACNA1E:p.G2080S,         CAPNS1:p.LV303del, CCDC159:p.A332S, CDKAL1:p.P409L, CDYL:p.V48A,         CDYL:p.A60G, CELSR2:p.L17P, CHD4:p.E138D, CKAP5:p.G576A,         CLCC1:p.K52R, CMTM8:p.S26T, CNKSR2:p.P249L, CNTN5:p.I501T,         COG5:p.H617R, COL15A1:p.K708R, COL6A3:p.A2378D, CRYGB:p.R143G,         CSGALNACT2:p.L362F, CUL4A:p.I438F, CXXC1:p.Q156H,         CYP19A1:p.F406L, DCLRE1B:p.F28I, DDX11:p.A376T, DDX11:p.E680D,         DEPDC5:p.R1525Q, DLC1:p.S741T, DNMT1:p.R995Q, DOCK11:p.Q169E,         DSPP:p.D1047N, E2F7:p.I91S, EBF1:p.D353G, ECI2:p.K55R,         EEF1A2:p.Y418S, EIF3J:p.A8G, EML6:p.K805R, EPAS1:p.S474T,         EPRS:p.L1335I, ERICH1:p.E327K, FAM101B:p.L5P, FAM104A:p.M1R,         FAM110D:p.R71H, FAM155A:p.Q95R, FAM186A:p.G1492E,         FAM194B:p.Y139H, FAM21B:p.P1231S, FAM32A:p.K9R, FAM46B:p.H416R,         FAM48B1:p.I499V, FAM48B1:p.A516P, FAM5C:p.S425W,         FAM86C2P:p.C120Y, FBXL14:p.V48G, FRMPD3:p.Q832del, FRS2:p.L47S,         GDF5:p.E105fs, GPNMB:p.C3fs, GPT2:p.R10P, H2AFV:p.Q125R,         HDLBP:p.R503C, HERC2:p.R2129C, HIST1H2BJ:p.K13R, HLX:p.N231K,         HMGB3:p.E198D, HSF4:p.R169W, HSF4:p.S491P, HYAL4:p.D222N,         INO80E:p.P206fs, INTS4:p.S460A, IQCF6:p.R3H, ITPR1:p.M1569I,         ITPR3:p.R1698G, KANSL3:p.G376E, KCNA4:p.E627del, KDM5A:p.P423S,         KDM6A:p.Y362fs, KIAA0020:p.K63R, KIDINS220:p.N851 S,         KIT:p.W557G, KLHDC2:p.W321S, KRAS:p.A146T, KRAS:p.Q61H,         KRAS:p.Q61L, KRAS:p.G12A, KRAS:p.G12R, KRBA1:p.R839G,         KRTAP4-8:p.T63S, L2HGDH:p.P441del, LAMC3:p.P174Q, LHCGR:p.L16Q,         LOC401296:p.L144M, LPHN2:p.F906I, LRP12:p.G310C, LTB4R:p.F73L,         LTBP3:p.L35del, LUC7L3:p.S148T, LYPD4:p.T64K, MAMLD1:p.Q572L,         MAP4K2:p.R341G, MAPK7:p.A501D, MAT2A:p.E166G, MED12L:p.C1292Y,         MESP2:p.Q182E, MEX3C:p.R534S, MIER2:p.L131F, MLL5:p.Y66C,         MLLT3:p.177_178SS>S, MMS19:p.D1005N, MRPS25:p.E119del,         MSH6:p.D576A, MTIF3:p.G65E, MUC17:p.M1807T, MUC17:p.T2279N,         MUC17:p.G2474S, MUC2:p.TTPSPP1475del, MUC2:p.T1568M,         MUC2:p.T1580N, MUC2:p.T1704I, MUC2:p.T1706M, MUC4:p.H1117D,         MUC5B:p.R1097H, MYEF2:p.K323E, MYEOV:p.L302H, MYH8:p.A785V,         MYO1A:p.N584K, NAP1L3:p.P353R, NAV1:p.I1433M, NCAM1:p.E131G,         NEB:p.D3107N, NEFH:p.V670E, NELL2:p.G170D, NHS:p.D1561N,         NKD2:p.H447del, NSD1:p.T461R, NT5C3:p.A3P, NYAP1:p.P480S,         OBSCN:p.A908T, OR10J1:p.R244Q, OR1S2:p.M298I, OR2L3:p.K294R,         OR6K6:p.F311L, PABPC3:p.V325fs, PBX2:p.Y262F, PCDHB4:p.P255F,         PCMTD1:p.V281A, PCP4L1:p.K64R, PDE3A:p.A98E, PDIA6:p.N56K,         PDS5A:p.L1309F, PHLDA2:p.R28S, PIGR:p.V183G, PIK3CA:p.E545K,         PIK3CD:p.C381R, PKD1:p.T938M, PLEKHM1:p.A895V, PLEKHN1:p.A600D,         PLXND1:p.R367L, PMS2:p.K651R, PNMA3:p.E200G, POTEF:p.S112G,         PRAMEF8:p.I448V, PRDM2:p.E278D, PRODH:p.L527V, PRPF31:p.R289W,         PSME4:p.N495D, PTGR1:p.E40A, PTPRB:p.Q726H, RABGEF1:p.N207D,         RAC1:p.P34R, RANBP17:p.M900I, REV3L:p.A30S, RFC3:p.I82N,         RFC3:p.K296N, RIMBP3:p.Q1154R, RPL19:p.R151C, RPL5:p.R58fs,         RPTN:p.M538I, RRAD:p.A278E, RYR1:p.D668Y, RYR2:p.L2023F,         SAFB:p.G799V, SCRIB:p.G332V, SDK1:p.Y2146C, SEC16A:p.T443K,         SEC31B:p.P905S, SELO:p.R565Q, SELP:p.A297T, SI:p.I1681K,         SLC2A7:p.H268Q, SLC37A1:p.V528I, SLC38A1:p.G100R,         SMARCA2:p.D1158A, SMARCA5:p.T156fs, SMC3:p.E970Q, SMG1:p.P2696H,         SNRNP200:p.A2129G, SPIN2B:p.M150V, ST6GALNAC1:p.S354N,         STAMBPL1:p.Y143H, STARD8:p.G662A, STON1-GTF2A1L:p.N451S,         SYMPK:p.A336G, TAS2R8:p.W98C, TCHH:p.W1016R, TET1:p.T1472S,         TIAM1:p.G247M, TNS1:p.P183S, TOR1AIP2:p.G146R, TPRX1:p.S216P,         TPRX1:p.S200P, TRMT61A:p.S244I, TSPAN4:p.L92V, TTF1:p.Q530R,         UBE2M:p.G131D, UBR5:p.R2517S, UGT2B11:p.R447I, UMODL1:p.M559I,         UNC93A:p.V445A, USP46:p.Q137R, VWA2:p.G317D, VWA7:p.V792G,         WASH3P:p.L187V, WNT5B:p.K327E, WRN:p.E510D, XDH:p.P410S,         ZAN:p.S755P, ZC3H11A:p.I777T, ZC3H7A:p.C575S, ZDHHC11:p.H250Q,         ZFHX4:p.D3239N, ZKSCAN3:p.K200A, ZMYM4:p.T367I, ZNF174:p.P353T,         ZNF322:p.Y353C, ZNF592:p.K324Q, ZNF592:p.P500T, ZNF782:p.C145F,         ZNF799:p.C453R, ZNF804B:p.P644S, and ZNRF3:p.R889W.

70. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from THCA; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         BRAF:p.V600E, NRAS:p.Q61R, HRAS:p.Q61R, NRAS:p.Q61K,         OTUD4:p.T909I, HRAS:p.Q61K, NLRP6:p.E611G, AKT1:p.E17K,         ANKMY1:p.N302I, ATP6V1A:p.L237P, CYP19A1:p.S113I,         DCUN1D4:p.L275P, DGCR8:p.E518K, DLC1:p.S741T, DNAH10:p.C1853F,         EIF1AX:p.G9D, FAM75D5:p.L222P, FCGRT:p.P40A, KRAS:p.Q61K,         LMX1B:p.Q285del, MAS1L:p.R324G, MED15:p.S35I, MEGF6:p.Y393C,         ODZ2:p.A1529V, OR5L1:p.R122H, OR6K6:p.F311L, OTX1:p.D315N,         POTEE:p.S75G, SCN5A:p.D1978H, TOP2A:p.K1199E, and         TSG101:p.K265R.

71. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from UCS; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         TP53:p.R248Q, ZNF814:p.D404E, BTN2A3P:p.P3S, FBXW7:p.R465C,         FRG1B:p.G65E, MUC4:p.H4205Q, NBPF10:p.V99F, PIK3CA:p.E545K,         PIK3CA:p.H1047R, PPP2R1A:p.P179R, DDX11L2:p.*128Q,         FBXW7:p.R479Q, FRG1B:p.K13N, FRG1B:p.L52S, HSD17B7P2:p.N175S,         KRAS:p.G12V, LOC283788:p.S37G, TP53:p.R273H, TP53:p.S241Y,         ADAMTS12:p.E359K, BCL2L11:p.L187fs, CDC27:p.L460fs,         CHEK2:p.K373E, ESPNP:p.W122fs, FBXW7:p.R689W, FBXW7:p.R505G,         FBXW7:p.R465H, FCGBP:p.V4019M, FRG1B:p.I10T, FRG1B:p.D32V,         FRG1B:p.R37K, KRAS:p.G12D, LOC100233156:p.R21C,         LOC283788:p.I46M, LRP1B:p.L1392F, MAMLD1:p.Q572L,         MST1P9:p.L319P, MUC4:p.A2390T, MUC4:p.G2172S, NBPF10:p.E3455K,         PIK3CA:p.G106V, PODXL:p.28_30PSP>P, POTEC:p.R477Q,         PPP2R1A:p.R183W, PPP2R1A:p.S219L, PTPN18:p.TG378del,         RGPD3:p.N756D, RPL13AP20:p.G107R, SAMD4B:p.R477W,         SMAP1:p.E169fs, TP53:p.H193R, TP53:p.H179R, TP53:p.R175H,         TUBBP5:p.R119H, and U2AF1:p.S34F.

72. The pharmaceutical composition of any of paragraphs 30-36, wherein:

-   -   (a) the population of subjects is suffering from PAAD; and     -   (b) the at least one tumor-specific mutation comprises any         combination of mutations selected from the group consisting of         RBM14:p.AAAAAAA286del, KRAS:p.G12D, JMY:p.PPPPPPPPPPPP811 del,         RIOK1:p.D69del, LCE2A:p.SSGGCCGSSSGGCC47del, KRAS:p.G12V,         C1QB:p.GPKGPMGPKGGPGAPGAP90del, ZFHX3:p.V777del,         DBR1:p.541_542DD>D, AEBP1:p.K1133del, KRAS:p.G12R,         RBM47:p.495_502AAAAAAAA>A, AP3S1:p.K41fs,         MLL2:p.AEGPHLSPQPEELHLSPQ792del, RFX1:p.386_401GGGGGGGGGGGGSG>G,         AXDND1:p.EQ991del, HERC2P3:p.A803V, RGPD3:p.N756D,         FNDC1:p.D180del, ANAPC1:p.T537A, IRS4:p.21_22AA>A,         GIGYF2:p.Q1005del, NCOA3:p.Q1253fs, SIK3:p.950_951QQ>Q,         GPR6:p.AAAAATAAGGPDTGEWGPPA36del, NBPF12:p.D1323fs,         SHROOM4:p.1156_1157EE>E, ZMIZ2:p.VAAAAATATATATAT153del,         DGKK:p.PAPP41del, LZTS1:p.RTQDLEGALRTKGLEL432del,         CASQ2:p.395_396DD>D, DCP1B:p.251_252insH,         ESPNP:p.296_317PPPPSFPPPPPPPGTQLPPPPP>P, KBTBD6:p.T403K,         NBPF16:p.D449fs, ANKRD36C:p.H438R,         ESPN:p.PPPPPPSFPPPPPPPGTQLPP430del, FCGBP:p.A2493V, KRAS:p.Q61H,         NCOA3:p.Q276del, OR2T2:p.C203fs, TMCC1:p.Q565L, BCKDHA:p.G129fs,         ESPNP:p.H64fs, GNAS:p.R844H, NBPF14:p.R25C, OGFOD1:p.G477fs,         RBM12:p.P693S, SLC38A10:p.1071_107211>I, SORBS2:p.P866S,         TP53:p.R248W, TP53:p.R175H, and UBAC1:p.E269del.

73. The pharmaceutical composition of any of paragraphs 30-72, wherein the composition comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, or at least 30 neoantigenic peptides.

74. The pharmaceutical composition of paragraph 73, wherein the composition comprises 15 to 20 neoantigenic peptides.

75. The pharmaceutical composition of paragraphs 73 or 74, further comprising at least one additional neoantigenic peptide which is specific for an individual patient's tumor.

76. The pharmaceutical composition of paragraph 75, wherein the patient specific neoantigenic peptide is selected by identifying sequence differences between the genome, exome, and/or transcriptome of the patient's tumor sample and the genome, exome, and/or transcriptome of a non-tumor sample.

77. The pharmaceutical composition of paragraph 75, wherein the samples are fresh or formalin-fixed paraffin embedded tumor tissues, freshly isolated cells, or circulating tumor cells.

78. The pharmaceutical composition of paragraph 75, wherein the sequence differences are determined by Next Generation Sequencing.

79. The pharmaceutical composition of any of paragraphs 30-78, wherein each neoantigenic peptide is from about 5 to about 50 amino acids in length.

80. The pharmaceutical composition of paragraph 79, wherein each neoantigenic peptide is between about 15 to about 35 amino acids in length; is about 15 amino acids or less in length; is about 8 and about 11 amino acids in length; or is 9 or 10 amino acids in length.

81. The pharmaceutical composition of paragraph 79 or 80, wherein each neoantigenic peptide binds major histocompatibility complex (MHC) class I.

82. The pharmaceutical composition of any one of paragraphs 30-81, wherein each neoantigenic peptide binds to MHC class I with a binding affinity of less than about 500 nM, or optionally each neoantigenic peptide binds to HLA-A, -B or -C with a K_(D) of less than 500 nM.

83. The pharmaceutical composition of paragraph 79, wherein each neoantigenic peptide is about 30 amino acids or less in length; is between about 6 and about 25 amino acids in length; is between about 15 and about 24 amino acids in length; or is between about 9 and about 15 amino acids in length.

84. The pharmaceutical composition of paragraph 79, 82 or 83, wherein each neoantigenic peptide binds major histocompatibility complex (MHC) class II.

85. The pharmaceutical composition of paragraph 84, wherein each neoantigenic peptide binds to MHC class I with a binding affinity of less than about 500 nM, or optionally each neoantigenic peptide binds to HLA-A, -B or -C with a K_(D) of less than 500 nM.

86. The pharmaceutical composition of any of paragraphs 30-85, wherein at least one neoantigenic peptide further comprises flanking amino acids.

87. The pharmaceutical composition of paragraph 86, wherein the flanking amino acids are not native flanking amino acids.

88. The pharmaceutical composition of any of paragraphs 30-87, which at least one neoantigenic peptide is linked to at least a second neoantigenic peptide.

89. The pharmaceutical composition of paragraph 88, wherein peptides are linked using a poly-glycine or poly-serine linker.

90. The pharmaceutical composition of paragraph 88 or 89, wherein the second neoantigenic peptide binds MHC class I or class II with a binding affinity of less than about 1000 nM.

91. The pharmaceutical composition of any of paragraphs 88-90, wherein the second neoantigenic peptide binds MHC class I or class II with a binding affinity of less than about 500 nM.

92. The pharmaceutical composition of any of paragraphs 88-91, wherein both of the neoepitopes bind to human leukocyte antigen (HLA)-A, -B, -C, -DP, -DQ, or -DR.

93. The pharmaceutical composition of any of paragraphs 88-92, wherein the isolated neoantigenic peptide and the second neoantigenic peptide binds a class I HLA or the isolated neoantigenic peptide and the second neoantigenic peptide binds a class II HLA.

94. The pharmaceutical composition of any of paragraphs 88-92, wherein the isolated neoantigenic peptide binds a class II HLA and the second neoantigenic peptide binds a class I HLA or the isolated neoantigenic peptide binds a class I HLA and the second neoantigenic peptide binds a class II HLA.

95. The pharmaceutical composition of any of paragraphs 30-94, wherein at least one neoantigenic peptide further comprises modifications which increase in vivo half-life, cellular targeting, antigen uptake, antigen processing, MHC affinity, MHC stability, or antigen presentation.

96. The pharmaceutical composition of paragraph 95, wherein the modification is conjugation to a carrier protein, conjugation to a ligand, conjugation to an antibody, PEGylation, polysialylation HESylation, recombinant PEG mimetics, Fc fusion, albumin fusion, nanoparticle attachment, nanoparticulate encapsulation, cholesterol fusion, iron fusion, acylation, amidation, glycosylation, side chain oxidation, phosphorylation, biotinylation, the addition of a surface active material, the addition of amino acid mimetics, or the addition of unnatural amino acids.

97. The pharmaceutical composition of paragraph 95, wherein the cells that are targeted are antigen presenting cells.

98. The pharmaceutical composition of paragraph 97, wherein the antigen presenting cells are dendritic cells.

99. The pharmaceutical composition of paragraph 98, wherein the dendritic cells are targeted using DEC205, XCR1, CD197, CD80, CD86, CD123, CD209, CD273, CD283, CD289, CD184, CD85h, CD85j, CD85k, CD85d, CD85g, CD85a, CD141, CD11c, CD83, TSLP receptor, or CD1a marker.

100. The pharmaceutical composition of paragraph 99, wherein the dendritic cells are targeted using the CD141, DEC205, or XCR1 marker.

101. The pharmaceutical composition of any of paragraphs 30-100, which is an immunogenic or vaccine composition.

102. The pharmaceutical composition of paragraph 101, further comprising an immunomodulator or adjuvant.

103. The pharmaceutical composition of paragraph 102, wherein the immunodulator or adjuvant is selected from the group consisting of Poly(I:C), Poly-ICLC, STING agonist, 1018 ISS, aluminium salts, Amplivax, AS15, BCG, CP-870,893, CpG7909, CyaA, dSLIM, GM-CSF, IC30, IC31, Imiquimod, ImuFact IMP321, IS Patch, ISS, ISCOMATRIX, JuvImmune, LipoVac, MF59, monophosphoryl lipid A, Montanide IMS 1312 VG, Montanide ISA 206 VG, Montanide ISA 50 V2, Montanide ISA 51 VG, OK-432, OM-174, OM-197-MP-EC, ISA-TLR2 agonist, ONTAK, PepTel®. vector system, PLG microparticles, resiquimod, SRL172, virosomes and other virus-like particles, YF-17D, VEGF trap, R848, beta-glucan, Pam3Cys, Pam3CSK4, acrylic or methacrylic polymers, copolymers of maleic anhydride, and QS21 stimulon.

104. An isolated polynucleotide encoding the isolated neoantigenic peptide of any of paragraphs 1-24.

105. The isolated polynucleotide of paragraph 104, which is RNA.

106. The isolated polynucleotide of paragraph 105, wherein the RNA is modified to increase stability, increase cellular targeting, increase translation efficiency, adjuvanticity, cytosol accessibility, and/or decrease cytotoxicity.

107. The isolated polynucleotide of paragraph 106, wherein the modification is conjugation to a carrier protein, conjugation to a ligand, conjugation to an antibody, codon optimization, increased GC-content, incorporation of modified nucleosides, incorporation of 5′-cap or cap analog, and/or incorporation of an unmasked poly-A sequence.

108. A cell comprising the polynucleotide of any of paragraphs 104-107.

109. A vector comprising the polynucleotide of any one of paragraphs 104-107.

110. The vector of paragraph 110, in which the polynucleotide is operably linked to a promoter.

111. The vector of paragraphs 109 or 110, which is a plasmid, phage, transposon, cosmid, virus, or virion.

112. The vector of paragraph 111, which is an adeno-associated virus, herpesvirus, lentivirus, or pseudotypes thereof.

113. An in vivo delivery system comprising the isolated polynucleotide of any of paragraphs 104-107.

114. The delivery system of paragraph 113, wherein the delivery system includes spherical nucleic acids, viruses, virus-like particles, plasmids, bacterial plasmids, or nanoparticles.

115. A cell comprising the vector or delivery system of any of paragraphs 109-114.

116. The cell of paragraph 115, which is an antigen presenting cell.

117. The cell of paragraph 116, which is a dendritic cell.

118. The cell of paragraph 117, which is an immature dendritic cell.

119. A composition comprising at least one polynucleotide of any of paragraphs 104-107.

120. The composition of paragraph 119, wherein the composition comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, or at least 30 of the isolated polynucleotides.

121. The composition of paragraph 120, wherein the composition comprises between about 2 and about 20 polynucleotides.

122. The composition of any one of paragraphs 119-121, wherein the composition further comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, or at least 30 additional neoantigenic polynucleotides encoding for additional neoantigenic peptides.

123. The composition of paragraph 122, wherein the composition comprises between about 4 and about 20 additional neoantigenic polynucleotides.

124. The composition of paragraph 122, wherein the isolated polynucleotides and the additional neoantigenic polynucleotides are linked.

125. The composition of paragraph 124, wherein the polynucleotides are linked using nucleic acids that encode a poly-glycine or poly-serine linker.

126. The composition of any of paragraphs 122-125, wherein at least one of the additional neoantigenic peptide is specific for an individual patient's tumor.

127. The composition of paragraph 126, wherein the patient specific neoantigenic peptide is selected by identifying sequence differences between the genome, exome, and/or transcriptome of the patient's tumor sample and the genome, exome, and/or transcriptome of a non-tumor sample.

128. The composition of paragraph 127, wherein the samples are fresh or formalin-fixed paraffin embedded tumor tissues, freshly isolated cells, or circulating tumor cells.

129. The composition of paragraphs 127 or 128, wherein the sequence differences are determined by Next Generation Sequencing.

130. A T cell receptor (TCR) capable of binding at least one neoantigenic peptide listed in any of paragraphs 1-27, optionally a neoantigenic peptide comprising FGFR3 S249C, ERBB3 V104M, EGFR L858R, MUC4 H4205Q, PDGFRA R483fs, TMEM52 23_26LLPL>L, or PODXL 28_30PSP>P.

131. The TCR of paragraph 130, which is capable of binding the isolated neoantigenic peptide in the context of MHC class I or class II.

132. A chimeric antigen receptor comprising: (i) a T cell activation molecule; (ii) a transmembrane region; and (iii) an antigen recognition moiety capable of binding an isolated neoantigenic peptide of any one of paragraphs 1-27.

133. The chimeric antigen receptor of paragraph 132, wherein CD3-zeta is the T cell activation molecule.

134. The chimeric antigen receptor of paragraph 132 or 133, further comprising at least one costimulatory signaling domain.

135. The chimeric antigen receptor of any of paragraphs 132-134, wherein the signaling domain is CD28, 4-1BB, ICOS, OX40, ITAM, or Fc epsilon RI-gamma.

136. The chimeric antigen receptor of any of paragraphs 132-135, wherein the antigen recognition moiety is capable of binding the isolated neoantigenic peptide in the context of MHC class I or class II.

137. The chimeric antigen receptor of any of paragraphs 132-136, comprising the CD3-zeta, CD28, CTLA-4, ICOS, BTLA, KIR, LAG3, CD137, OX40, CD27, CD40L, Tim-3, A2aR, or PD-1 transmembrane region.

138. The chimeric antigen receptor of any of paragraphs 132-137, wherein the tumor-specific epitope is located in the extracellular domain of a tumor associated polypeptide, optionally the tumor-specific epitope comprises FGFR3 S249C, ERBB3 V104M, EGFR L858R, MUC4 H4205Q, PDGFRA R483fs, TMEM52 23_26LLPL>L, or PODXL 28_30PSP>P.

139. A T cell comprising the T cell receptor or chimeric antigen receptor of any of paragraphs 130-138.

140. The T cell of paragraph 139, which is a helper or cytotoxic T cell.

141. A nucleic acid comprising a promoter operably linked to a polynucleotide encoding the T cell receptor of paragraph 130 or 131.

142. The nucleic acid of paragraph 141, wherein the TCR is capable of binding the at least one neoantigenic peptide in the context of major histocompatibility complex (MHC) class I or class II.

143. A nucleic acid comprising a promoter operably linked to a polynucleotide encoding the chimeric antigen receptor of any of paragraphs 132-138.

144. The nucleic acid of paragraph 143, wherein the antigen recognition moiety is capable of binding the at least one neoantigenic peptide in the context of major histocompatibility complex (MHC) class I or class II.

145. The nucleic acid of paragraphs 143 or 144, wherein the tumor-specific epitope is located in the extracellular domain of a tumor associated polypeptide.

146. The nucleic acid of any of paragraphs 143-145, comprising the CD3-zeta, CD28, CTLA-4, ICOS, BTLA, KIR, LAG3, CD137, OX40, CD27, CD40L, Tim-3, A2aR, or PD-1 transmembrane region.

147. An antibody capable of binding at least one neoantigenic peptide listed in Tables 1-9.

148. A modified cell transfected or transduced with the nucleic acid of any one of paragraphs 141-146.

149. The modified cell of paragraph 148, wherein the modified cell is a T cell, tumor infiltrating lymphocyte, NK-T cell, TCR-expressing cell, CD4+ T cell, CD8+ T cell, or NK cell.

150. A composition comprising the T cell receptor or chimeric antigen receptor of any of paragraphs 130-138.

151. A composition comprising autologous patient T cells containing the T cell receptor or chimeric antigen receptor of any of paragraphs 130-138.

152. The composition of paragraph 150 or 151, further comprising an immune checkpoint inhibitor.

153. The composition of paragraph 150 of 151, further comprising at least two immune checkpoint inhibitors.

154. The composition of paragraph 152 or 153, wherein the immune checkpoint inhibitor inhibits a checkpoint protein selected from the group consisting of CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, and B-7 family ligands or a combination thereof.

155. The composition of paragraph 154, wherein the immune checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from the group consisting of CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, and B-7 family ligands or a combination thereof.

156. The composition of any of paragraphs 119-129 or 150-156, further comprising an immune modulator or adjuvant.

157. The composition of paragraph 156, wherein the immune modulator is a co-stimulatory ligand, a TNF ligand, an Ig superfamily ligand, CD28, CD80, CD86, ICOS, CD40L, OX40, CD27, GITR, CD30, DR3, CD69, or 4-1BB.

158. The composition of paragraph 156, wherein the immune modulator is at least one cancer cell or cancer cell extract.

159. The composition of paragraph 158, wherein the cancer cell is autologous to the subject in need of the composition.

160. The composition of paragraph 159, wherein the cancer cell has undergone lysis or been exposed to UV radiation.

161. The composition of paragraph 156, wherein the composition further comprises an adjuvant.

162. The composition of paragraph 161, wherein the adjuvant is selected from the group consisting of: Poly(I:C), Poly-ICLC, STING agonist, 1018 ISS, aluminium salts, Amplivax, AS15, BCG, CP-870,893, CpG7909, CyaA, dSLIM, GM-CSF, IC30, IC31, Imiquimod, ImuFact IMP321, IS Patch, ISS, ISCOMATRIX, Juvlmmune, LipoVac, MF59, monophosphoryl lipid A, Montanide IMS 1312 VG, Montanide ISA 206 VG, Montanide ISA 50 V2, Montanide ISA 51 VG, OK-432, OM-174, OM-197-MP-EC, ISA-TLR2 agonist, ONTAK, PepTel®. vector system, PLG microparticles, resiquimod, SRL172, virosomes and other virus-like particles, YF-17D, VEGF trap, R848, beta-glucan, Pam3Cys, Pam3CSK4, acrylic or methacrylic polymers, copolymers of maleic anhydride, and QS21 stimulon.

163. The composition of paragraph 161 or 162, wherein the adjuvant induces a humoral immune response when administered to a subject.

164. The composition of paragraph 162, wherein the adjuvant induces a T helper cell type I response when administered to a subject.

165. An in vivo delivery system comprising the pharmaceutical composition of any of paragraphs 30-103.

166. The delivery system of paragraph 165, wherein the delivery system includes cell-penetrating peptides, nanoparticulate encapsulation, virus like particles, or liposomes.

167. The delivery system of paragraph 166, wherein the cell-penetrating peptide is TAT peptide, herpes simplex virus VP22, transportan, or Antp.

168. A cell comprising the isolated neoantigenic peptide of any of paragraphs 1-29.

169. The cell of paragraph 168, which is an antigen presenting cell.

170. The cell of paragraph 169, which is a dendritic cell.

171. A method of treating cancer or initiating, enhancing, or prolonging an anti-tumor responses in a subject in need thereof comprising administering to the subject the peptide, polynucleotide, vector, composition, antibody, or cells of any of paragraphs 1-164.

172. A method of prophylactic cancer treatment comprising:

-   -   (a) selecting a cancer drug for a patient in need thereof, the         drug selected from the group consisting of ibrutinib, erlotinib,         imatinib, gefitinib, crizotinib, trastuzumab, vemurafenib,         RAF/MEK inhibitors, and antiestrogen therapy, and     -   (b) administering prophylactically to the subject, a         pharmaceutical composition according to any of paragraphs 30-103         wherein the at least one neoantigenic peptide is derived from         drug resistant mutations associated with the selected cancer         drug.

173. A method of treating or preventing a tumor in a population of subjects in need thereof, comprising administering to a subject an agent comprising an extracellular ligand-binding domain recognizing a tumor-specific neoepitope comprising a tumor-specific mutation having an incidence of at least 1% of subjects in the population.

174. The method according to any of paragraphs 171-173, wherein the tumor-specific mutation comprises a mutation listed for any population in Table 9.

175. The method according to any of paragraphs 171-173, wherein the tumor-specific mutation is within a gene containing an extracellular domain.

176. The method according to paragraph 175, wherein the tumor-specific mutation comprises FGFR3 S249C, ERBB3 V104M, EGFR L858R, MUC4 H4205Q, PDGFRA R483fs, TMEM52 23_26LLPL>L, or PODXL 28_30PSP>P.

177. The method according to paragraph 176, wherein the tumor-specific mutation is within the extracellular domain.

178. The method according to paragraph 177, wherein the tumor-specific mutation comprises FGFR3 S249C or ERBB3 V104M.

179. The method of any of paragraph 171-178, wherein the subject is a human.

180. The method of paragraph 179, wherein the subject has cancer.

181. The method of paragraph 180, wherein the cancer is selected from the group consisting of urogenital, gynecological, lung, gastrointestinal, head and neck cancer, malignant glioblastoma, malignant mesothelioma, non-metastatic or metastatic breast cancer, malignant melanoma, Merkel Cell Carcinoma or bone and soft tissue sarcomas, haematologic neoplasias, multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome and acute lymphoblastic leukemia, non-small cell lung cancer (NSCLC), breast cancer, metastatic colorectal cancers, hormone sensitive or hormone refractory prostate cancer, colorectal cancer, ovarian cancer, hepatocellular cancer, renal cell cancer, pancreatic cancer, gastric cancer, oesophageal cancers, hepatocellular cancers, cholangiocellular cancers, head and neck squamous cell cancer soft tissue sarcoma, and small cell lung cancer.

182. The method of any of paragraphs 171-181, wherein the subject has undergone surgical removal of the tumor.

183. The method of any of paragraphs 171-182, wherein the peptide, polynucleotide, vector, composition, or cells is administered via intravenous, intraperitoneal, intratumoral, intradermal, or subcutaneous administration.

184. The method of paragraph 183, wherein the peptide, polynucleotide, vector, composition, or cells is administered into an anatomic site that drains into a lymph node basin.

185. The method of paragraph 184, wherein administration is into multiple lymph node basins.

186. The method of any one of paragraphs 183-185, wherein administration is by a subcutaneous or intradermal route.

187. The method of paragraph 183, wherein peptide is administered.

188. The method of paragraph 187, wherein administration is intratumorally.

189. The method of paragraph 183, wherein polynucleotide, optionally RNA, is administered.

190. The method of paragraph 189, wherein the polynucleotide is administered intravenously.

191. The method of paragraph 183, wherein the cell is a T cell or dendritic cell.

192. The method of paragraph 191, wherein the peptide or polynucleotide comprises an antigen presenting cell targeting moiety.

193. The method of any of paragraphs 171-192, further comprising administering at least one immune checkpoint inhibitor to the subject.

194. The method of paragraph 193, wherein the checkpoint inhibitor is a biologic therapeutic or a small molecule.

195. The method of paragraph 193 or 194, wherein the checkpoint inhibitor is selected from the group consisting of a monoclonal antibody, a humanized antibody, a fully human antibody and a fusion protein or a combination thereof.

196. The method of any of paragraphs 193-195, wherein the checkpoint inhibitor inhibits a checkpoint protein selected from the group consisting of CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, and B-7 family ligands or a combination thereof.

197. The method of any of paragraphs 193-196, wherein the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from the group consisting of CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, and B-7 family ligands or a combination thereof.

198. The method of any of paragraphs 193-197, wherein two or more checkpoint inhibitors are administered.

199. The method of paragraph 198, wherein the checkpoint inhibitors are: (i) ipilimumab or tremelimumab, and (ii) nivolumab.

200. The method of any of paragraphs 193-199, wherein the checkpoint inhibitor and the composition are administered simultaneously or sequentially in any order.

201. The method of paragraph 200, wherein the peptide, polynucleotide, vector, composition, or cells is administered prior to the checkpoint inhibitor.

202. The method of paragraph 200, wherein the peptide, polynucleotide, vector, composition, or cells is administered after the checkpoint inhibitor.

203. The method of paragraph 200, wherein administration of the checkpoint inhibitor is continued throughout neoantigen peptide, polynucleotide, vector, composition, or cell therapy.

204. The method of any of paragraphs 193-203, wherein the neoantigen peptide, polynucleotide, vector, composition, or cell therapy is administered to subjects that only partially respond or do not respond to checkpoint inhibitor therapy.

205. The method of any one of paragraphs 193-204, wherein the checkpoint inhibitor is administered intravenously or subcutaneously.

206. The method of paragraph 205, wherein the checkpoint inhibitor is administered subcutaneously within about 2 cm of the site of administration of the composition.

207. The method of paragraph 206, wherein the composition is administered into the same draining lymph node as the checkpoint inhibitor.

208. The method of any of paragraphs 171-207, further comprising administering an additional therapeutic agent to the subject either prior to, simultaneously with, or after treatment with the peptide, polynucleotide, vector, composition, or cells.

209. The method of paragraph 208, wherein the additional agent is a chemotherapeutic agent, an immunomodulatory drug, an immune metabolism modifying drug, a targeted therapy, radiation an anti-angiogenesis agent, or an agent that reduces immune-suppression.

210. The method of paragraph 209, wherein the chemotherapeutic agent is an alkylating agent, a topoisomerase inhibitor, an anti-metabolite, or an anti-mitotic agent.

211. The method of paragraph 208, wherein the additional agent is an anti-glucocorticoid induced tumor necrosis factor family receptor (GITR) agonistic antibody or antibody fragment, ibrutinib, docetaxeol, cisplatin, or cyclophosphamide.

212. The method of any of paragraphs 171-211, which elicits a CD4+ T cell immune response.

213. The method of any of paragraphs 171-212, which elicits a CD4+ T cell immune response and a CD8+ T cell immune response.

214. A method for stimulating an immune response in a subject, comprising administering an effective amount of modified cells or composition of any of paragraphs 30-103, 108, 115-129, 139, 140, 148-164, and 168-170.

215. The method of paragraph 214, wherein the immune response is cytotoxic and/or humoral immune response.

216. The method of paragraph 214, wherein the method stimulates a T cell-mediated immune response in a subject.

217. The method of paragraph 216, wherein the T cell-mediated immune response is directed against a target cell.

218. The method of paragraph 217, wherein the target cell is a tumor cell.

219. The method of any of paragraphs 214-218, wherein the modified cells are transfected or transduced in vivo.

220. The method of any of paragraphs 214-219, wherein the modified cells are transfected or transduced ex vivo.

221. The method of any of paragraphs 214-220, wherein the modified cells are autologous patient T cells.

222. The method of paragraph 221, wherein the autologous patient T cells are obtained from a patient that has received a neoantigen peptide or nucleic acid vaccine.

223. The method of paragraph 222, wherein the neoantigen peptide or nucleic acid vaccine comprises at least one personalized neoantigen.

224. The method of paragraph 223, wherein the neoantigen peptide or nucleic acid vaccine comprises at least one additional neoantigenic peptide listed in Tables 1-9.

225. The method of paragraph 224, wherein the patient received a chemotherapeutic agent, an immunomodulatory drug, an immune metabolism modifying drug, targeted therapy or radiation prior to and/or during receipt of the neoantigen peptide or nucleic acid vaccine.

226. The method of any of paragraphs 222-225, wherein the patient receives treatment with at least one checkpoint inhibitor.

227. The method of any of paragraphs 222-226, wherein the autologous T cells are obtained from a patient that has already received at least one round of T cell therapy containing a neoantigen.

228. The method of any of paragraphs 222-227, wherein the method further comprises adoptive T cell therapy.

229. The method of paragraph 228, wherein the adoptive T cell therapy comprises autologous T-cells.

230. The method of paragraph 229, wherein the autologous T-cells are targeted against tumor antigens.

231. The method of paragraph 228 or 229 wherein the adoptive T cell therapy further comprises allogenic T-cells.

232. The method of paragraph 231, wherein the allogenic T-cells are targeted against tumor antigens.

233. The method of any of paragraphs 227-231, wherein the adoptive T cell therapy is administered before the checkpoint inhibitor.

234. A method for evaluating the efficacy of any of paragraphs 171-213, comprising: (i) measuring the number or concentration of target cells in a first sample obtained from the subject before administering the modified cell, (ii) measuring the number concentration of target cells in a second sample obtained from the subject after administration of the modified cell, and (iii) determining an increase or decrease of the number or concentration of target cells in the second sample compared to the number or concentration of target cells in the first sample.

235. The method of paragraph 234, wherein treatment efficacy is determined by monitoring a clinical outcome; an increase, enhancement or prolongation of anti-tumor activity by T cells; an increase in the number of anti-tumor T cells or activated T cells as compared with the number prior to treatment; B cell activity; CD4 T cell activity; or a combination thereof.

236. The method of paragraph 235, wherein treatment efficacy is determined by monitoring a biomarker.

237. The method of paragraph 236, wherein the biomarker is selected from the group consisting of CEA, Her-2/neu, bladder tumor antigen, thyroglobulin, alpha-fetoprotein, PSA, CA 125, CA19.9, CA 15.3, leptin, prolactin, osteopontin, IGF-II, CD98, fascin, sPIgR, 14-3-3 eta, troponin I, and b-type natriuretic peptide.

238. The method of paragraph 235, wherein clinical outcome is selected from the group consisting of tumor regression; tumor shrinkage; tumor necrosis; anti-tumor response by the immune system; tumor expansion, recurrence or spread; or a combination thereof.

239. The method of paragraph 235, wherein the treatment effect is predicted by presence of T cells or by presence of a gene signature indicating T cell inflammation or a combination thereof.

240. A kit comprising a neoantigen therapeutic of any of paragraphs 1-164.

Accordingly, it is an object of the invention not to encompass within the invention any previously known product, process of making the product, or method of using the product such that Applicants reserve the right and hereby disclose a disclaimer of any previously known product, process, or method. It is further noted that the invention does not intend to encompass within the scope of the invention any product, process, or making of the product or method of using the product, which does not meet the written description and enablement requirements of the USPTO (35 U.S.C. § 112, first paragraph) or the EPO (Article 83 of the EPC), such that Applicants reserve the right and hereby disclose a disclaimer of any previously described product, process of making the product, or method of using the product. It may be advantageous in the practice of the invention to be in compliance with Art. 53(c) EPC and Rule 28(b) and (c) EPC. All rights to explicitly disclaim any embodiments that are the subject of any granted patent(s) of applicant in the lineage of this application or in any other lineage or in any prior filed application of any third party is explicitly reserved Nothing herein is to be construed as a promise.

It is noted that in this disclosure and particularly in the claims and/or paragraphs, terms such as “comprises”, “comprised”, “comprising” and the like can have the meaning attributed to it in U.S. Patent law; e.g., they can mean “includes”, “included”, “including”, and the like; and that terms such as “consisting essentially of” and “consists essentially of” have the meaning ascribed to them in U.S. Patent law, e.g., they allow for elements not explicitly recited, but exclude elements that are found in the prior art or that affect a basic or novel characteristic of the invention. Nothing herein is intended as a promise.

These and other embodiments are disclosed or are obvious from and encompassed by, the following Detailed Description.

DETAILED DESCRIPTION OF THE INVENTION

To facilitate an understanding of the present invention, a number of terms and phrases are defined herein:

Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein are modified by the term about.

Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive. Unless specifically stated or obvious from context, as used herein, the terms “a,” “an,” and “the” are understood to be singular or plural.

All gene name symbols refer to the gene as commonly known in the art. Gene symbols may be those referred to by the HUGO Gene Nomenclature Committee (HGNC). Any reference to the gene symbol is a reference made to the entire gene or variants of the gene. The HUGO Gene Nomenclature Committee is responsible for providing human gene naming guidelines and approving new, unique human gene names and symbols. All human gene names and symbols can be searched at www.genenames.org, the HGNC website, and the guidelines for their formation are available there (www.genenames.org/guidelines).

By “agent” is meant any small molecule chemical compound, antibody, nucleic acid molecule, or polypeptide, or fragments thereof.

By “ameliorate” is meant decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a neoplasia, tumor, etc.).

By “alteration” is meant a change (increase or decrease) in the expression levels or activity of a gene or polypeptide as detected by standard art known methods such as those described herein. As used herein, an alteration includes a 10% change in expression levels, preferably a 25% change, more preferably a 40% change, and most preferably a 50% or greater change in expression levels.

By “analog” is meant a molecule that is not identical, but has analogous functional or structural features. For example, a tumor specific neo-antigen polypeptide analog retains the biological activity of a corresponding naturally-occurring tumor specific neo-antigen polypeptide, while having certain biochemical modifications that enhance the analog's function relative to a naturally-occurring polypeptide. Such biochemical modifications could increase the analog's protease resistance, membrane permeability, or half-life, without altering, for example, ligand binding. An analog may include an unnatural amino acid.

“Combination therapy” is intended to embrace administration of therapeutic agents (e.g. neoantigenic peptides described herein) in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents. For example, one combination of the present invention may comprise a pooled sample of neoantigenic peptides administered at the same or different times, or they can be formulated as a single, co-formulated pharmaceutical composition comprising the peptides. As another example, a combination of the present invention (e.g., a pooled sample of tumor specific neoantigens) may be formulated as separate pharmaceutical compositions that can be administered at the same or different time. As used herein, the term “simultaneously” is meant to refer to administration of one or more agents at the same time. For example, in certain embodiments, the neoantigenic peptides are administered simultaneously. Simultaneously includes administration contemporaneously, that is during the same period of time. In certain embodiments, the one or more agents are administered simultaneously in the same hour, or simultaneously in the same day. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, sub-cutaneous routes, intramuscular routes, direct absorption through mucous membrane tissues (e.g., nasal, mouth, vaginal, and rectal), and ocular routes (e.g., intravitreal, intraocular, etc.). The therapeutic agents can be administered by the same route or by different routes. For example, one component of a particular combination may be administered by intravenous injection while the other component(s) of the combination may be administered orally. The components may be administered in any therapeutically effective sequence. The phrase “combination” embraces groups of compounds or non-drug therapies useful as part of a combination therapy.

The term “neoantigen” or “neoantigenic” means a class of tumor antigens that arises from a tumor-specific mutation(s) which alters the amino acid sequence of genome encoded proteins.

By “neoplasia” is meant any disease that is caused by or results in inappropriately high levels of cell division, inappropriately low levels of apoptosis, or both. For example, cancer is an example of a neoplasia. Examples of cancers include, without limitation, leukemia (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease, non-Hodgkin's disease), Waldenstrom's macroglobulinemia, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, nile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodenroglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma). Lymphoproliferative disorders are also considered to be proliferative diseases.

The term “vaccine” is meant to refer in the present context to a pooled sample of tumor-specific neoantigenic peptides, for example at least two, at least three, at least four, at least five, or more neoantigenic peptides. A “vaccine” is to be understood as meaning a composition for generating immunity for the prophylaxis and/or treatment of diseases (e.g., neoplasia/tumor). Accordingly, vaccines are medicaments which comprise antigens and are intended to be used in humans or animals for generating specific defense and protective substance by vaccination. A “vaccine composition” can include a pharmaceutically acceptable excipient, carrier or diluent.

The term “pharmaceutically acceptable” refers to approved or approvable by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, including humans.

A “pharmaceutically acceptable excipient, carrier or diluent” refers to an excipient, carrier or diluent that can be administered to a subject, together with an agent, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the agent.

A “pharmaceutically acceptable salt” of pooled tumor specific neoantigens as recited herein may be an acid or base salt that is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication. Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids. Specific pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzene sulfonic, ethane disulfonic, 2-hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkanoic such as acetic, HOOC—(CH2)n-COOH where n is 0-4, and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those of ordinary skill in the art will recognize from this disclosure and the knowledge in the art that further pharmaceutically acceptable salts for the pooled tumor specific neoantigens provided herein, including those listed by Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985). In general, a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in an appropriate solvent.

By a “polypeptide” or “peptide” is meant a polypeptide that has been separated from components that naturally accompany it. Typically, the polypeptide is isolated when it is at least 60%, by weight, free from the proteins and naturally-occurring organic molecules with which it is naturally associated. Preferably, the preparation is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight, a polypeptide. An isolated polypeptide may be obtained, for example, by extraction from a natural source, by expression of a recombinant nucleic acid encoding such a polypeptide; or by chemically synthesizing the protein. Purity can be measured by any appropriate method, for example, column chromatography, polyacrylamide gel electrophoresis, or by HPLC analysis.

As used herein, the terms “prevent,” “preventing,” “prevention,” “prophylactic treatment,” and the like, refer to reducing the probability of developing a disease or condition in a subject, who does not have, but is at risk of or susceptible to developing a disease or condition.

The term “prime/boost” or “prime/boost dosing regimen” is meant to refer to the successive administrations of a vaccine or immunogenic or immunological compositions. The priming administration (priming) is the administration of a first vaccine or immunogenic or immunological composition type and may comprise one, two or more administrations. The boost administration is the second administration of a vaccine or immunogenic or immunological composition type and may comprise one, two or more administrations, and, for instance, may comprise or consist essentially of annual administrations. In certain embodiments, administration of the neoplasia vaccine or immunogenic composition is in a prime/boost dosing regimen.

Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, “nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 may comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

A “receptor” is to be understood as meaning a biological molecule or a molecule grouping capable of binding a ligand. A receptor may serve, to transmit information in a cell, a cell formation or an organism. The receptor comprises at least one receptor unit and frequently contains two or more receptor units, where each receptor unit may consist of a protein molecule, in particular a glycoprotein molecule. The receptor has a structure that complements the structure of a ligand and may complex the ligand as a binding partner. Signaling information may be transmitted by conformational changes of the receptor following binding with the ligand on the surface of a cell. According to the invention, a receptor may refer to particular proteins of MHC classes I and II capable of forming a receptor/ligand complex with a ligand, in particular a peptide or peptide fragment of suitable length.

The term “subject” refers to an animal which is the object of treatment, observation, or experiment. By way of example only, a subject includes, but is not limited to, a mammal, including, but not limited to, a human or a non-human mammal, such as a non-human primate, bovine, equine, canine, ovine, or feline.

The terms “treat,” “treated,” “treating,” “treatment,” and the like are meant to refer to reducing or ameliorating a disorder and/or symptoms associated therewith (e.g., a neoplasia or tumor). “Treating” may refer to administration of the therapy to a subject after the onset, or suspected onset, of a cancer. “Treating” includes the concepts of “alleviating”, which refers to lessening the frequency of occurrence or recurrence, or the severity, of any symptoms or other ill effects related to a cancer and/or the side effects associated with cancer therapy. The term “treating” also encompasses the concept of “managing” which refers to reducing the severity of a particular disease or disorder in a patient or delaying its recurrence, e.g., lengthening the period of remission in a patient who had suffered from the disease. It is appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition, or symptoms associated therewith be completely eliminated.

The term “therapeutic effect” refers to some extent of relief of one or more of the symptoms of a disorder (e.g., a neoplasia or tumor) or its associated pathology. “Therapeutically effective amount” as used herein refers to an amount of an agent which is effective, upon single or multiple dose administration to the cell or subject, in prolonging the survivability of the patient with such a disorder, reducing one or more signs or symptoms of the disorder, preventing or delaying, and the like beyond that expected in the absence of such treatment. “Therapeutically effective amount” is intended to qualify the amount required to achieve a therapeutic effect. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the “therapeutically effective amount” (e.g., ED50) of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in a pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

The terms “spacer” or “linker” as used in reference to a fusion protein refers to a peptide that joins the proteins comprising a fusion protein. Generally, a spacer has no specific biological activity other than to join or to preserve some minimum distance or other spatial relationship between the proteins or RNA sequences. However, in certain embodiments, the constituent amino acids of a spacer may be selected to influence some property of the molecule such as the folding, net charge, or hydrophobicity of the molecule.

Suitable linkers for use in an embodiment of the present invention are well known to those of skill in the art and include, but are not limited to, straight or branched-chain carbon linkers, heterocyclic carbon linkers, or peptide linkers. The linker is used to separate two neoantigenic peptides by a distance sufficient to ensure that, in a preferred embodiment, each neoantigenic peptide properly folds. Preferred peptide linker sequences adopt a flexible extended conformation and do not exhibit a propensity for developing an ordered secondary structure. Typical amino acids in flexible protein regions include Gly, Asn and Ser. Virtually any permutation of amino acid sequences containing Gly, Asn and Ser would be expected to satisfy the above criteria for a linker sequence. Other near neutral amino acids, such as Thr and Ala, also may be used in the linker sequence. Still other amino acid sequences that may be used as linkers are disclosed in Maratea et al. (1985), Gene 40: 39-46; Murphy et al. (1986) Proc. Nat'l. Acad. Sci. USA 83: 8258-62; U.S. Pat. Nos. 4,935,233; and 4,751,180.

The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

Any compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.

The therapy disclosed herein constitutes a new method for treating various types of cancer. The therapy described herein also provides a method of therapy for achieving clinical benefit without an unacceptable level of side effects.

In one aspect the present invention relates to methods for the treatment of neoplasia, and more particularly tumors, by administering to a subject a vaccine or immunogenic composition comprising a plurality of tumor specific neoantigenic peptides. As described in more detail herein, in some embodiments the composition provides a specific, optimized subset of tumor-specific neoantigens suitable for the treatment of tumors in a high proportion of subjects suffering from cancer. In some embodiments, the tumor specific neoantigens may together bind to a high overall proportion of HLA allotypes present in the subject population.

The immune system can be classified into two functional subsystems: the innate and the acquired immune system. The innate immune system is the first line of defense against infections, and most potential pathogens are rapidly neutralized by this system before they can cause, for example, a noticeable infection. The acquired immune system reacts to molecular structures, referred to as antigens, of the intruding organism. There are two types of acquired immune reactions, which include the humoral immune reaction and the cell-mediated immune reaction. In the humoral immune reaction, antibodies secreted by B cells into bodily fluids bind to pathogen-derived antigens, leading to the elimination of the pathogen through a variety of mechanisms, e.g. complement-mediated lysis. In the cell-mediated immune reaction, T-cells capable of destroying other cells are activated. For example, if proteins associated with a disease are present in a cell, they are fragmented proteolytically to peptides within the cell. Specific cell proteins then attach themselves to the antigen or peptide formed in this manner and transport them to the surface of the cell, where they are presented to the molecular defense mechanisms, in particular T-cells, of the body. Cytotoxic T cells recognize these antigens and kill the cells that harbor the antigens.

The molecules that transport and present peptides on the cell surface are referred to as proteins of the major histocompatibility complex (MHC). MHC proteins are classified into two types, referred to as MHC class I and MHC class II. The structures of the proteins of the two MHC classes are very similar; however, they have very different functions. Proteins of MHC class I are present on the surface of almost all cells of the body, including most tumor cells. MHC class I proteins are loaded with antigens that usually originate from endogenous proteins or from pathogens present inside cells, and are then presented to naïve or cytotoxic T-lymphocytes (CTLs). MHC class II proteins are present on dendritic cells, B-lymphocytes, macrophages and other antigen-presenting cells. They mainly present peptides, which are processed from external antigen sources, i.e. outside of the cells, to T-helper (Th) cells. Most of the peptides bound by the MHC class I proteins originate from cytoplasmic proteins produced in the healthy host cells of an organism itself, and do not normally stimulate an immune reaction. Accordingly, cytotoxic T-lymphocytes that recognize such self-peptide-presenting MHC molecules of class I are deleted in the thymus (central tolerance) or, after their release from the thymus, are deleted or inactivated, i.e. tolerized (peripheral tolerance). MHC molecules are capable of stimulating an immune reaction when they present peptides to non-tolerized T-lymphocytes. Cytotoxic T-lymphocytes have both T-cell receptors (TCR) and CD8 molecules on their surface. T-Cell receptors are capable of recognizing and binding peptides complexed with the molecules of MHC class I. Each cytotoxic T-lymphocyte expresses a unique T-cell receptor which is capable of binding specific MHC/peptide complexes.

The peptide antigens attach themselves to the molecules of MHC class I by competitive affinity binding within the endoplasmic reticulum, before they are presented on the cell surface. Here, the affinity of an individual peptide antigen is directly linked to its amino acid sequence and the presence of specific binding motifs in defined positions within the amino acid sequence. If the sequence of such a peptide is known, it is possible to manipulate the immune system against diseased cells using, for example, peptide vaccines.

One of the critical barriers to developing curative and tumor-specific immunotherapy is the identification and selection of highly specific and restricted tumor antigens to avoid autoimmunity. Tumor neoantigens, which arise as a result of genetic change (e.g., inversions, translocations, deletions, missense mutations, splice site mutations, etc.) within malignant cells, represent the most tumor-specific class of antigens. Neoantigens have rarely been used in cancer vaccine or immunogenic compositions due to technical difficulties in identifying them, selecting optimized neoantigens, and producing neoantigens for use in a vaccine or immunogenic composition. These problems may be addressed by:

-   -   identifying mutations in neoplasias/tumors which are present at         the DNA level in tumor but not in matched germline samples from         a high proportion of subjects having cancer;     -   analyzing the identified mutations with one or more peptide-MHC         binding prediction algorithms to generate a plurality of         neoantigen T cell epitopes that are expressed within the         neoplasia/tumor and that bind to a high proportion of patient         HLA alleles; and     -   synthesizing the plurality of neoantigenic peptides selected         from the sets of all neoantigen peptides and predicted binding         peptides for use in a cancer vaccine or immunogenic composition         suitable for treating a high proportion of subjects having         cancer.

For example, translating sequencing information into a therapeutic vaccine may include:

(1) Prediction of mutated peptides that can bind to HLA molecules of a high proportion of individuals. Efficiently choosing which particular mutations to utilize as immunogen requires the ability to predict which mutated peptides would efficiently bind to a high proportion of patient's HLA alleles. Recently, neural network based learning approaches with validated binding and non-binding peptides have advanced the accuracy of prediction algorithms for the major HLA-A and -B alleles.

(2) Formulating the drug as a multi-epitope vaccine of long peptides. Targeting as many mutated epitopes as practically possible takes advantage of the enormous capacity of the immune system, prevents the opportunity for immunological escape by down-modulation of a particular immune targeted gene product, and compensates for the known inaccuracy of epitope prediction approaches. Synthetic peptides provide a particularly useful means to prepare multiple immunogens efficiently and to rapidly translate identification of mutant epitopes to an effective vaccine. Peptides can be readily synthesized chemically and easily purified utilizing reagents free of contaminating bacteria or animal substances. The small size allows a clear focus on the mutated region of the protein and also reduces irrelevant antigenic competition from other components (unmutated protein or viral vector antigens).

(3) Combination with a strong vaccine adjuvant. Effective vaccines require a strong adjuvant to initiate an immune response. As described below, poly-ICLC, an agonist of TLR3 and the RNA helicase-domains of MDA5 and RIG3, has shown several desirable properties for a vaccine adjuvant. These properties include the induction of local and systemic activation of immune cells in vivo, production of stimulatory chemokines and cytokines, and stimulation of antigen-presentation by DCs. Furthermore, poly-ICLC can induce durable CD4+ and CD8+ responses in humans. Importantly, striking similarities in the upregulation of transcriptional and signal transduction pathways were seen in subjects vaccinated with poly-ICLC and in volunteers who had received the highly effective, replication-competent yellow fever vaccine. Furthermore, >90% of ovarian carcinoma patients immunized with poly-ICLC in combination with a NYES0-1 peptide vaccine (in addition to Montanide) showed induction of CD4+ and CD8+ T cell, as well as antibody responses to the peptide in a recent phase 1 study. At the same time, polylCLC has been extensively tested in more than 25 clinical trials to date and exhibited a relatively benign toxicity profile.

The above-described advantages of the invention are described further herein.

As described herein, there is a large body of evidence in both animals and humans that mutated epitopes are effective in inducing an immune response and that cases of spontaneous tumor regression or long term survival correlate with CD8+ T-cell responses to mutated epitopes (Buckwalter and Srivastava P K. “It is the antigen(s), stupid” and other lessons from over a decade of vaccitherapy of human cancer. Seminars in immunology 20:296-300 (2008); Karanikas et al, High frequency of cytolytic T lymphocytes directed against a tumor-specific mutated antigen detectable with HLA tetramers in the blood of a lung carcinoma patient with long survival. Cancer Res. 61:3718-3724 (2001); Lennerz et al, The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. Proc Natl Acad Sci USA. 102:16013 (2005)) and that “immunoediting” can be tracked to alterations in expression of dominant mutated antigens in mice and man (Matsushita et al, Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting Nature 482:400 (2012); DuPage et al, Expression of tumor-specific antigens underlies cancer immunoediting Nature 482:405 (2012); and Sampson et al, Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma J Clin Oncol. 28:4722-4729 (2010)).

Sequencing technology has revealed that each tumor contains multiple, patient-specific mutations that alter the protein coding content of a gene. Such mutations create altered proteins, ranging from single amino acid changes (caused by missense mutations) to addition of long regions of novel amino acid sequence due to frame shifts, read-through of termination codons or translation of intron regions (novel open reading frame mutations; neoORFs). These mutated proteins are valuable targets for the host's immune response to the tumor as, unlike native proteins, they are not subject to the immune-dampening effects of self-tolerance. Therefore, mutated proteins are more likely to be immunogenic and are also more specific for the tumor cells compared to normal cells of the patient.

In one embodiment, the neoantigenic peptides in the composition together have affinity to a plurality of MHC molecules, e.g. which together cover a large proportion of the target population. Efficiently choosing which particular mutations to utilize as immunogen requires the ability to predict which mutated peptides would efficiently bind to the HLA alleles present in the patient population. Recently, neural network based learning approaches with validated binding and non-binding peptides have advanced the accuracy of prediction algorithms for the major HLA-A and -B alleles. Utilizing the recently improved algorithms for predicting which missense mutations create strong binding peptides to cognate MHC molecules, a set of peptides representative of optimal mutated epitopes (both neoORF and missense) for the patient population may be identified and prioritized (Zhang et al, Machine learning competition in immunology—Prediction of HLA class I binding peptides J Immunol Methods 374:1 (2011); Lundegaard et al Prediction of epitopes using neural network based methods J Immunol Methods 374:26 (2011)).

Targeting as many mutated epitopes as practically possible takes advantage of the enormous capacity of the immune system, prevents the opportunity for immunological escape by down-modulation of a particular immune targeted gene product, and compensates for the known inaccuracy of epitope prediction approaches. Synthetic peptides provide a particularly useful means to prepare multiple immunogens efficiently and to rapidly translate identification of mutant epitopes to an effective vaccine or immunogenic composition. Peptides can be readily synthesized chemically and easily purified utilizing reagents free of contaminating bacteria or animal substances. The small size allows a clear focus on the mutated region of the protein and also reduces irrelevant antigenic competition from other components (unmutated protein or viral vector antigens).

In one embodiment the drug formulation is a multi-epitope vaccine or immunogenic composition of long peptides. Such “long” peptides undergo efficient internalization, processing and cross-presentation in professional antigen-presenting cells such as dendritic cells, and have been shown to induce CTLs in humans (Melief and van der Burg, Immunotherapy of established (pre) malignant disease by synthetic long peptide vaccines Nature Rev Cancer 8:351 (2008)). In one embodiment at least 2 peptides are prepared for immunization. In some embodiments 20 or more peptides are prepared for immunization. In one embodiment the neoantigenic peptide ranges from about 5 to about 50 amino acids in length. In another embodiment peptides from about 15 to about 35 amino acids in length is synthesized. In preferred embodiment the neoantigenic peptide ranges from about 20 to about 35 amino acids in length.

Production of Tumor Specific Neoantigens

The present invention is based, at least in part, on the ability to present the immune system of the patient with a pool of tumor specific neoantigens. One of skill in the art from this disclosure and the knowledge in the art will appreciate that there are a variety of ways in which to produce such tumor specific neoantigens. In general, such tumor specific neoantigens may be produced either in vitro or in vivo. Tumor specific neoantigens may be produced in vitro as peptides or polypeptides, which may then be formulated into a neoplasia vaccine or immunogenic composition and administered to a subject. As described in further detail herein, such in vitro production may occur by a variety of methods known to one of skill in the art such as, for example, peptide synthesis or expression of a peptide/polypeptide from a DNA or RNA molecule in any of a variety of bacterial, eukaryotic, or viral recombinant expression systems, followed by purification of the expressed peptide/polypeptide. Alternatively, tumor specific neoantigens may be produced in vivo by introducing molecules (e.g., DNA, RNA, viral expression systems, and the like) that encode tumor specific neoantigens into a subject, whereupon the encoded tumor specific neoantigens are expressed. The methods of in vitro and in vivo production of neoantigens is also further described herein as it relates to pharmaceutical compositions and methods of delivery of the therapy.

In certain embodiments the present invention includes modified neoantigenic peptides. As used herein in reference to neoantigenic peptides, the terms “modified”, “modification” and the like refer to one or more changes that enhance a desired property of the neoantigenic peptide, where the change does not alter the primary amino acid sequence of the neoantigenic peptide. “Modification” includes a covalent chemical modification that does not alter the primary amino acid sequence of the neoantigenic peptide itself. Such desired properties include, for example, prolonging the in vivo half-life, increasing the stability, reducing the clearance, altering the immunogenicity or allergenicity, enabling the raising of particular antibodies, cellular targeting, antigen uptake, antigen processing, MHC affinity, MHC stability, or antigen presentation. Changes to a neoantigenic peptide that may be carried out include, but are not limited to, conjugation to a carrier protein, conjugation to a ligand, conjugation to an antibody, PEGylation, polysialylation HESylation, recombinant PEG mimetics, Fc fusion, albumin fusion, nanoparticle attachment, nanoparticulate encapsulation, cholesterol fusion, iron fusion, acylation, amidation, glycosylation, side chain oxidation, phosphorylation, biotinylation, the addition of a surface active material, the addition of amino acid mimetics, or the addition of unnatural amino acids.

The clinical effectiveness of protein therapeutics is often limited by short plasma half-life and susceptibility to protease degradation. Studies of various therapeutic proteins (e.g., filgrastim) have shown that such difficulties may be overcome by various modifications, including conjugating or linking the polypeptide sequence to any of a variety of non-proteinaceous polymers, e.g., polyethylene glycol (PEG), polypropylene glycol, or polyoxyalkylenes (see, for example, typically via a linking moiety covalently bound to both the protein and the nonproteinaceous polymer, e.g., a PEG). Such PEG-conjugated biomolecules have been shown to possess clinically useful properties, including better physical and thermal stability, protection against susceptibility to enzymatic degradation, increased solubility, longer in vivo circulating half-life and decreased clearance, reduced immunogenicity and antigenicity, and reduced toxicity.

PEGs suitable for conjugation to a polypeptide sequence are generally soluble in water at room temperature, and have the general formula R(0-CH₂—CH₂)_(n)O—R, where R is hydrogen or a protective group such as an alkyl or an alkanol group, and where n is an integer from 1 to 1000. When R is a protective group, it generally has from 1 to 8 carbons. The PEG conjugated to the polypeptide sequence can be linear or branched. Branched PEG derivatives, “star-PEGs” and multi-armed PEGs are contemplated by the present disclosure. A molecular weight of the PEG used in the present disclosure is not restricted to any particular range, but certain embodiments have a molecular weight between 500 and 20,000 while other embodiments have a molecular weight between 4,000 and 10,000.

The present disclosure also contemplates compositions of conjugates wherein the PEGs have different n values and thus the various different PEGs are present in specific ratios. For example, some compositions comprise a mixture of conjugates where n=1, 2, 3 and 4. In some compositions, the percentage of conjugates where n=1 is 18-25%, the percentage of conjugates where n=2 is 50-66%, the percentage of conjugates where n=3 is 12-16%, and the percentage of conjugates where n=4 is up to 5%. Such compositions can be produced by reaction conditions and purification methods know in the art. For example, cation exchange chromatography may be used to separate conjugates, and a fraction is then identified which contains the conjugate having, for example, the desired number of PEGs attached, purified free from unmodified protein sequences and from conjugates having other numbers of PEGs attached.

PEG may be bound to a polypeptide of the present disclosure via a terminal reactive group (a “spacer”). The spacer is, for example, a terminal reactive group which mediates a bond between the free amino or carboxyl groups of one or more of the polypeptide sequences and polyethylene glycol. The PEG having the spacer which may be bound to the free amino group includes N-hydroxysuccinylimide polyethylene glycol which may be prepared by activating succinic acid ester of polyethylene glycol with N-hydroxy succinylimide. Another activated polyethylene glycol which may be bound to a free amino group is 2,4-bis(0-methoxypolyethyleneglycol)-6-chloro-s-triazine which may be prepared by reacting polyethylene glycol monomethyl ether with cyanuric chloride. The activated polyethylene glycol which is bound to the free carboxyl group includes polyoxyethylenediamine.

Conjugation of one or more of the polypeptide sequences of the present disclosure to PEG having a spacer may be carried out by various conventional methods. For example, the conjugation reaction can be carried out in solution at a pH of from 5 to 10, at temperature from 4° C. to room temperature, for 30 minutes to 20 hours, utilizing a molar ratio of reagent to protein of from 4:1 to 30:1. Reaction conditions may be selected to direct the reaction towards producing predominantly a desired degree of substitution. In general, low temperature, low pH (e.g., pH=5), and short reaction time tend to decrease the number of PEGs attached, whereas high temperature, neutral to high pH (e.g., pH>7), and longer reaction time tend to increase the number of PEGs attached. Various means known in the art may be used to terminate the reaction. In some embodiments the reaction is terminated by acidifying the reaction mixture and freezing at, e.g., −20° C.

The present disclosure also contemplates the use of PEG Mimetics. Recombinant PEG mimetics have been developed that retain the attributes of PEG (e.g., enhanced serum half-life) while conferring several additional advantageous properties. By way of example, simple polypeptide chains (comprising, for example, Ala, Glu, Gly, Pro, Ser and Thr) capable of forming an extended conformation similar to PEG can be produced recombinantly already fused to the peptide or protein drug of interest (e.g., Amunix′ XTEN technology; Mountain View, Calif.). This obviates the need for an additional conjugation step during the manufacturing process. Moreover, established molecular biology techniques enable control of the side chain composition of the polypeptide chains, allowing optimization of immunogenicity and manufacturing properties.

For purposes of the present disclosure, “glycosylation” is meant to broadly refer to the enzymatic process that attaches glycans to proteins, lipids or other organic molecules. The use of the term “glycosylation” in conjunction with the present disclosure is generally intended to mean adding or deleting one or more carbohydrate moieties (either by removing the underlying glycosylation site or by deleting the glycosylation by chemical and/or enzymatic means), and/or adding one or more glycosylation sites that may or may not be present in the native sequence. In addition, the phrase includes qualitative changes in the glycosylation of the native proteins involving a change in the nature and proportions of the various carbohydrate moieties present. Glycosylation can dramatically affect the physical properties of proteins and can also be important in protein stability, secretion, and subcellular localization. Proper glycosylation can be essential for biological activity. In fact, some genes from eucaryotic organisms, when expressed in bacteria (e.g., E. coli) which lack cellular processes for glycosylating proteins, yield proteins that are recovered with little or no activity by virtue of their lack of glycosylation.

Addition of glycosylation sites can be accomplished by altering the amino acid sequence. The alteration to the polypeptide may be made, for example, by the addition of, or substitution by, one or more serine or threonine residues (for O-linked glycosylation sites) or asparagine residues (for N-linked glycosylation sites). The structures of N-linked and O-linked oligosaccharides and the sugar residues found in each type may be different. One type of sugar that is commonly found on both is N-acetylneuraminic acid (hereafter referred to as sialic acid). Sialic acid is usually the terminal residue of both N-linked and O-linked oligosaccharides and, by virtue of its negative charge, may confer acidic properties to the glycoprotein. A particular embodiment of the present disclosure comprises the generation and use of N-glycosylation variants.

The polypeptide sequences of the present disclosure may optionally be altered through changes at the DNA level, particularly by mutating the DNA encoding the polypeptide at preselected bases such that codons are generated that will translate into the desired amino acids. Another means of increasing the number of carbohydrate moieties on the polypeptide is by chemical or enzymatic coupling of glycosides to the polypeptide.

Removal of carbohydrates may be accomplished chemically or enzymatically, or by substitution of codons encoding amino acid residues that are glycosylated. Chemical deglycosylation techniques are known, and enzymatic cleavage of carbohydrate moieties on polypeptides can be achieved by the use of a variety of endo- and exo-glycosidases.

Dihydrofolate reductase (DHFR)—deficient Chinese Hamster Ovary (CHO) cells are a commonly used host cell for the production of recombinant glycoproteins. These cells do not express the enzyme beta-galactoside alpha-2,6-sialyltransferase and therefore do not add sialic acid in the alpha-2,6 linkage to N-linked oligosaccharides of glycoproteins produced in these cells.

The present disclosure also contemplates the use of polysialylation, the conjugation of peptides and proteins to the naturally occurring, biodegradable a-(2-8) linked polysialic acid (“PSA”) in order to improve their stability and in vivo pharmacokinetics. PSA is a biodegradable, non-toxic natural polymer that is highly hydrophilic, giving it a high apparent molecular weight in the blood which increases its serum half-life. In addition, polysialylation of a range of peptide and protein therapeutics has led to markedly reduced proteolysis, retention of activity in vivo activity, and reduction in immunogenicity and antigenicity (see, e.g., G. Gregoriadis et al., Int. J. Pharmaceutics 300(1-2): 125-30). As with modifications with other conjugates (e.g., PEG), various techniques for site-specific polysialylation are available (see, e.g., T. Lindhout et al., PNAS 108(18)7397-7402 (2011)).

Additional suitable components and molecules for conjugation include, for example, thyroglobulin; albumins such as human serum albumin (HAS); tetanus toxoid; Diphtheria toxoid; polyamino acids such as poly(D-lysine:D-glutamic acid): VP6 polypeptides of rotaviruses; influenza virus hemaglutinin, influenza virus nucleoprotein; Keyhole Limpet Hemocyanin (KLH); and hepatitis B virus core protein and surface antigen; or any combination of the foregoing.

Fusion of albumin to one or more polypeptides of the present disclosure can, for example, be achieved by genetic manipulation, such that the DNA coding for HSA, or a fragment thereof, is joined to the DNA coding for the one or more polypeptide sequences. Thereafter, a suitable host can be transformed or transfected with the fused nucleotide sequences in the form of, for example, a suitable plasmid, so as to express a fusion polypeptide. The expression may be effected in vitro from, for example, prokaryotic or eukaryotic cells, or in vivo from, for example, a transgenic organism. In some embodiments of the present disclosure, the expression of the fusion protein is performed in mammalian cell lines, for example, CHO cell lines. Transformation is used broadly herein to refer to the genetic alteration of a cell resulting from the direct uptake, incorporation and expression of exogenous genetic material (exogenous DNA) from its surroundings and taken up through the cell membrane(s). Transformation occurs naturally in some species of bacteria, but it can also be effected by artificial means in other cells.

Furthermore, albumin itself may be modified to extend its circulating half-life. Fusion of the modified albumin to one or more Polypeptides can be attained by the genetic manipulation techniques described above or by chemical conjugation; the resulting fusion molecule has a half-life that exceeds that of fusions with non-modified albumin. (See WO2011/051489).

Several albumin-binding strategies have been developed as alternatives for direct fusion, including albumin binding through a conjugated fatty acid chain (acylation). Because serum albumin is a transport protein for fatty acids, these natural ligands with albumin-binding activity have been used for half-life extension of small protein therapeutics. For example, insulin determir (LEVEMIR), an approved product for diabetes, comprises a myristyl chain conjugated to a genetically-modified insulin, resulting in a long-acting insulin analog.

Another type of modification is to conjugate (e.g., link) one or more additional components or molecules at the N- and/or C-terminus of a polypeptide sequence, such as another protein (e.g., a protein having an amino acid sequence heterologous to the subject protein), or a carrier molecule. Thus, an exemplary polypeptide sequence can be provided as a conjugate with another component or molecule.

A conjugate modification may result in a polypeptide sequence that retains activity with an additional or complementary function or activity of the second molecule. For example, a polypeptide sequence may be conjugated to a molecule, e.g., to facilitate solubility, storage, in vivo or shelf half-life or stability, reduction in immunogenicity, delayed or controlled release in vivo, etc. Other functions or activities include a conjugate that reduces toxicity relative to an unconjugated polypeptide sequence, a conjugate that targets a type of cell or organ more efficiently than an unconjugated polypeptide sequence, or a drug to further counter the causes or effects associated with a disorder or disease as set forth herein (e.g., diabetes).

A Polypeptide may also be conjugated to large, slowly metabolized macromolecules such as proteins; polysaccharides, such as sepharose, agarose, cellulose, cellulose beads; polymeric amino acids such as polyglutamic acid, polylysine; amino acid copolymers; inactivated virus particles; inactivated bacterial toxins such as toxoid from diphtheria, tetanus, cholera, leukotoxin molecules; inactivated bacteria; and dendritic cells.

Additional candidate components and molecules for conjugation include those suitable for isolation or purification. Particular non-limiting examples include binding molecules, such as biotin (biotin-avidin specific binding pair), an antibody, a receptor, a ligand, a lectin, or molecules that comprise a solid support, including, for example, plastic or polystyrene beads, plates or beads, magnetic beads, test strips, and membranes.

Purification methods such as cation exchange chromatography may be used to separate conjugates by charge difference, which effectively separates conjugates into their various molecular weights. For example, the cation exchange column can be loaded and then washed with −20 mM sodium acetate, pH −4, and then eluted with a linear (0 M to 0.5 M) NaCl gradient buffered at a pH from about 3 to 5.5, e.g., at pH −4.5. The content of the fractions obtained by cation exchange chromatography may be identified by molecular weight using conventional methods, for example, mass spectroscopy, SDS-PAGE, or other known methods for separating molecular entities by molecular weight.

In certain embodiments, the amino- or carboxyl-terminus of a polypeptide sequence of the present disclosure can be fused with an immunoglobulin Fc region (e.g., human Fc) to form a fusion conjugate (or fusion molecule). Fc fusion conjugates have been shown to increase the systemic half-life of biopharmaceuticals, and thus the biopharmaceutical product may require less frequent administration.

Fc binds to the neonatal Fc receptor (FcRn) in endothelial cells that line the blood vessels, and, upon binding, the Fc fusion molecule is protected from degradation and re-released into the circulation, keeping the molecule in circulation longer. This Fc binding is believed to be the mechanism by which endogenous IgG retains its long plasma half-life. More recent Fc-fusion technology links a single copy of a biopharmaceutical to the Fc region of an antibody to optimize the pharmacokinetic and pharmacodynamic properties of the biopharmaceutical as compared to traditional Fc-fusion conjugates.

The present disclosure contemplates the use of other modifications, currently known or developed in the future, of the Polypeptides to improve one or more properties. One such method for prolonging the circulation half-life, increasing the stability, reducing the clearance, or altering the immunogenicity or allergenicity of a polypeptide of the present disclosure involves modification of the polypeptide sequences by hesylation, which utilizes hydroxyethyl starch derivatives linked to other molecules in order to modify the molecule's characteristics. Various aspects of hesylation are described in, for example, U.S. Patent Appln. Nos. 2007/0134197 and 2006/0258607.

In Vitro Peptide/Polypeptide Synthesis

Proteins or peptides may be made by any technique known to those of skill in the art, including the expression of proteins, polypeptides or peptides through standard molecular biological techniques, the isolation of proteins or peptides from natural sources, in vitro translation, or the chemical synthesis of proteins or peptides. The nucleotide and protein, polypeptide and peptide sequences corresponding to various genes have been previously disclosed, and may be found at computerized databases known to those of ordinary skill in the art. One such database is the National Center for Biotechnology Information's Genbank and GenPept databases located at the National Institutes of Health website. The coding regions for known genes may be amplified and/or expressed using the techniques disclosed herein or as would be known to those of ordinary skill in the art. Alternatively, various commercial preparations of proteins, polypeptides and peptides are known to those of skill in the art.

Peptides can be readily synthesized chemically utilizing reagents that are free of contaminating bacterial or animal substances (Merrifield RB: Solid phase peptide synthesis. I. The synthesis of a tetrapeptide. J. Am. Chem. Soc. 85:2149-54, 1963). In certain embodiments, neoantigenic peptides are prepared by (1) parallel solid-phase synthesis on multi-channel instruments using uniform synthesis and cleavage conditions; (2) purification over a RP-HPLC column with column stripping; and re-washing, but not replacement, between peptides; followed by (3) analysis with a limited set of the most informative assays. The Good Manufacturing Practices (GMP) footprint can be defined around the set of peptides for an individual patient, thus requiring suite changeover procedures only between syntheses of peptides for different patients.

Alternatively, a nucleic acid (e.g., a polynucleotide) encoding a neoantigenic peptide of the invention may be used to produce the neoantigenic peptide in vitro. The polynucleotide may be, e.g., DNA, cDNA, PNA, CNA, RNA, either single- and/or double-stranded, or native or stabilized forms of polynucleotides, such as e.g. polynucleotides with a phosphorothiate backbone, or combinations thereof and it may or may not contain introns so long as it codes for the peptide. In one embodiment in vitro translation is used to produce the peptide. Many exemplary systems exist that one skilled in the art could utilize (e.g., Retic Lysate IVT Kit, Life Technologies, Waltham, Mass.).

An expression vector capable of expressing a polypeptide can also be prepared. Expression vectors for different cell types are well known in the art and can be selected without undue experimentation. Generally, the DNA is inserted into an expression vector, such as a plasmid, in proper orientation and correct reading frame for expression. If necessary, the DNA may be linked to the appropriate transcriptional and translational regulatory control nucleotide sequences recognized by the desired host (e.g., bacteria), although such controls are generally available in the expression vector. The vector is then introduced into the host bacteria for cloning using standard techniques (see, e.g., Sambrook et al. (1989) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.).

Expression vectors comprising the isolated polynucleotides, as well as host cells containing the expression vectors, are also contemplated. The neoantigenic peptides may be provided in the form of RNA or cDNA molecules encoding the desired neoantigenic peptides. One or more neoantigenic peptides of the invention may be encoded by a single expression vector.

The term “polynucleotide encoding a polypeptide” encompasses a polynucleotide which includes only coding sequences for the polypeptide as well as a polynucleotide which includes additional coding and/or non-coding sequences. Polynucleotides can be in the form of RNA or in the form of DNA. DNA includes cDNA, genomic DNA, and synthetic DNA; and can be double-stranded or single-stranded, and if single stranded can be the coding strand or non-coding (anti-sense) strand.

In embodiments, the polynucleotides may comprise the coding sequence for the tumor specific neoantigenic peptide fused in the same reading frame to a polynucleotide which aids, for example, in expression and/or secretion of a polypeptide from a host cell (e.g., a leader sequence which functions as a secretory sequence for controlling transport of a polypeptide from the cell). The polypeptide having a leader sequence is a preprotein and can have the leader sequence cleaved by the host cell to form the mature form of the polypeptide.

In embodiments, the polynucleotides can comprise the coding sequence for the tumor specific neoantigenic peptide fused in the same reading frame to a marker sequence that allows, for example, for purification of the encoded polypeptide, which may then be incorporated into the personalized neoplasia vaccine or immunogenic composition. For example, the marker sequence can be a hexa-histidine tag (SEQ ID NO: 33733) supplied by a pQE-9 vector to provide for purification of the mature polypeptide fused to the marker in the case of a bacterial host, or the marker sequence can be a hemagglutinin (HA) tag derived from the influenza hemagglutinin protein when a mammalian host (e.g., COS-7 cells) is used. Additional tags include, but are not limited to, Calmodulin tags, FLAG tags, Myc tags, S tags, SBP tags, Softag 1, Softag 3, V5 tag, Xpress tag, Isopeptag, SpyTag, Biotin Carboxyl Carrier Protein (BCCP) tags, GST tags, fluorescent protein tags (e.g., green fluorescent protein tags), maltose binding protein tags, Nus tags, Strep-tag, thioredoxin tag, TC tag, Ty tag, and the like.

In embodiments, the polynucleotides may comprise the coding sequence for one or more of the tumor specific neoantigenic peptides fused in the same reading frame to create a single concatamerized neoantigenic peptide construct capable of producing multiple neoantigenic peptides.

In certain embodiments, isolated nucleic acid molecules having a nucleotide sequence at least 60% identical, at least 65% identical, at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, or at least 96%, 97%, 98% or 99% identical to a polynucleotide encoding a tumor specific neoantigenic peptide of the present invention, can be provided.

By a polynucleotide having a nucleotide sequence at least, for example, 95% “identical” to a reference nucleotide sequence is intended that the nucleotide sequence of the polynucleotide is identical to the reference sequence except that the polynucleotide sequence can include up to five point mutations per each 100 nucleotides of the reference nucleotide sequence. In other words, to obtain a polynucleotide having a nucleotide sequence at least 95% identical to a reference nucleotide sequence, up to 5% of the nucleotides in the reference sequence can be deleted or substituted with another nucleotide, or a number of nucleotides up to 5% of the total nucleotides in the reference sequence can be inserted into the reference sequence. These mutations of the reference sequence can occur at the amino- or carboxy-terminal positions of the reference nucleotide sequence or anywhere between those terminal positions, interspersed either individually among nucleotides in the reference sequence or in one or more contiguous groups within the reference sequence.

As a practical matter, whether any particular nucleic acid molecule is at least 80% identical, at least 85% identical, at least 90% identical, and in some embodiments, at least 95%, 96%, 970%, 98%, or 99% identical to a reference sequence can be determined conventionally using known computer programs such as the Bestfit program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, 575 Science Drive, Madison, Wis. 53711). Bestfit uses the local homology algorithm of Smith and Waterman, Advances in Applied Mathematics 2:482-489 (1981), to find the best segment of homology between two sequences. When using Bestfit or any other sequence alignment program to determine whether a particular sequence is, for instance, 95% identical to a reference sequence according to the present invention, the parameters are set such that the percentage of identity is calculated over the full length of the reference nucleotide sequence and that gaps in homology of up to 5% of the total number of nucleotides in the reference sequence are allowed.

The isolated tumor specific neoantigenic peptides described herein can be produced in vitro (e.g., in the laboratory) by any suitable method known in the art. Such methods range from direct protein synthetic methods to constructing a DNA sequence encoding isolated polypeptide sequences and expressing those sequences in a suitable transformed host. In some embodiments, a DNA sequence is constructed using recombinant technology by isolating or synthesizing a DNA sequence encoding a wild-type protein of interest. Optionally, the sequence can be mutagenized by site-specific mutagenesis to provide functional analogs thereof. See, e.g. Zoeller et al., Proc. Nat'l. Acad. Sci. USA 81:5662-5066 (1984) and U.S. Pat. No. 4,588,585.

In embodiments, a DNA sequence encoding a polypeptide of interest would be constructed by chemical synthesis using an oligonucleotide synthesizer. Such oligonucleotides can be designed based on the amino acid sequence of the desired polypeptide and selecting those codons that are favored in the host cell in which the recombinant polypeptide of interest is produced. Standard methods can be applied to synthesize an isolated polynucleotide sequence encoding an isolated polypeptide of interest. For example, a complete amino acid sequence can be used to construct a back-translated gene. Further, a DNA oligomer containing a nucleotide sequence coding for the particular isolated polypeptide can be synthesized. For example, several small oligonucleotides coding for portions of the desired polypeptide can be synthesized and then ligated. The individual oligonucleotides typically contain 5′ or 3′ overhangs for complementary assembly.

Once assembled (e.g., by synthesis, site-directed mutagenesis, or another method), the polynucleotide sequences encoding a particular isolated polypeptide of interest is inserted into an expression vector and optionally operatively linked to an expression control sequence appropriate for expression of the protein in a desired host. Proper assembly can be confirmed by nucleotide sequencing, restriction mapping, and expression of a biologically active polypeptide in a suitable host. As well known in the art, in order to obtain high expression levels of a transfected gene in a host, the gene can be operatively linked to transcriptional and translational expression control sequences that are functional in the chosen expression host.

Recombinant expression vectors may be used to amplify and express DNA encoding the tumor specific neoantigenic peptides. Recombinant expression vectors are replicable DNA constructs which have synthetic or cDNA-derived DNA fragments encoding a tumor specific neoantigenic peptide or a bioequivalent analog operatively linked to suitable transcriptional or translational regulatory elements derived from mammalian, microbial, viral or insect genes. A transcriptional unit generally comprises an assembly of (1) a genetic element or elements having a regulatory role in gene expression, for example, transcriptional promoters or enhancers, (2) a structural or coding sequence which is transcribed into mRNA and translated into protein, and (3) appropriate transcription and translation initiation and termination sequences, as described in detail herein. Such regulatory elements can include an operator sequence to control transcription. The ability to replicate in a host, usually conferred by an origin of replication, and a selection gene to facilitate recognition of transformants can additionally be incorporated. DNA regions are operatively linked when they are functionally related to each other. For example, DNA for a signal peptide (secretory leader) is operatively linked to DNA for a polypeptide if it is expressed as a precursor which participates in the secretion of the polypeptide; a promoter is operatively linked to a coding sequence if it controls the transcription of the sequence; or a ribosome binding site is operatively linked to a coding sequence if it is positioned so as to permit translation. Generally, operatively linked means contiguous, and in the case of secretory leaders, means contiguous and in reading frame. Structural elements intended for use in yeast expression systems include a leader sequence enabling extracellular secretion of translated protein by a host cell. Alternatively, where recombinant protein is expressed without a leader or transport sequence, it can include an N-terminal methionine residue. This residue can optionally be subsequently cleaved from the expressed recombinant protein to provide a final product.

Useful expression vectors for eukaryotic hosts, especially mammals or humans include, for example, vectors comprising expression control sequences from SV40, bovine papilloma virus, adenovirus and cytomegalovirus. Useful expression vectors for bacterial hosts include known bacterial plasmids, such as plasmids from Escherichia coli, including pCR 1, pBR322, pMB9 and their derivatives, wider host range plasmids, such as M13 and filamentous single-stranded DNA phages.

Suitable host cells for expression of a polypeptide include prokaryotes, yeast, insect or higher eukaryotic cells under the control of appropriate promoters. Prokaryotes include gram negative or gram positive organisms, for example E. coli or bacilli. Higher eukaryotic cells include established cell lines of mammalian origin. Cell-free translation systems could also be employed. Appropriate cloning and expression vectors for use with bacterial, fungal, yeast, and mammalian cellular hosts are well known in the art (see Pouwels et al., Cloning Vectors: A Laboratory Manual, Elsevier, N.Y., 1985).

Various mammalian or insect cell culture systems are also advantageously employed to express recombinant protein. Expression of recombinant proteins in mammalian cells can be performed because such proteins are generally correctly folded, appropriately modified and completely functional. Examples of suitable mammalian host cell lines include the COS-7 lines of monkey kidney cells, described by Gluzman (Cell 23:175, 1981), and other cell lines capable of expressing an appropriate vector including, for example, L cells, C127, 3T3, Chinese hamster ovary (CHO), 293, HeLa and BHK cell lines. Mammalian expression vectors can comprise nontranscribed elements such as an origin of replication, a suitable promoter and enhancer linked to the gene to be expressed, and other 5′ or 3′ flanking nontranscribed sequences, and 5′ or 3′ nontranslated sequences, such as necessary ribosome binding sites, a polyadenylation site, splice donor and acceptor sites, and transcriptional termination sequences. Baculovirus systems for production of heterologous proteins in insect cells are reviewed by Luckow and Summers, Bio/Technology 6:47 (1988).

The proteins produced by a transformed host can be purified according to any suitable method. Such standard methods include chromatography (e.g., ion exchange, affinity and sizing column chromatography, and the like), centrifugation, differential solubility, or by any other standard technique for protein purification. Affinity tags such as hexahistidine (SEQ ID NO: 33733), maltose binding domain, influenza coat sequence, glutathione-S-transferase, and the like can be attached to the protein to allow easy purification by passage over an appropriate affinity column. Isolated proteins can also be physically characterized using such techniques as proteolysis, nuclear magnetic resonance and x-ray crystallography.

For example, supernatants from systems which secrete recombinant protein into culture media can be first concentrated using a commercially available protein concentration filter, for example, an Amicon or Millipore Pellicon ultrafiltration unit. Following the concentration step, the concentrate can be applied to a suitable purification matrix. Alternatively, an anion exchange resin can be employed, for example, a matrix or substrate having pendant diethylaminoethyl (DEAE) groups. The matrices can be acrylamide, agarose, dextran, cellulose or other types commonly employed in protein purification. Alternatively, a cation exchange step can be employed. Suitable cation exchangers include various insoluble matrices comprising sulfopropyl or carboxymethyl groups. Finally, one or more reversed-phase high performance liquid chromatography (RP-HPLC) steps employing hydrophobic RP-HPLC media, e.g., silica gel having pendant methyl or other aliphatic groups, can be employed to further purify a cancer stem cell protein-Fc composition. Some or all of the foregoing purification steps, in various combinations, can also be employed to provide a homogeneous recombinant protein.

Recombinant protein produced in bacterial culture can be isolated, for example, by initial extraction from cell pellets, followed by one or more concentration, salting-out, aqueous ion exchange or size exclusion chromatography steps. High performance liquid chromatography (HPLC) can be employed for final purification steps. Microbial cells employed in expression of a recombinant protein can be disrupted by any convenient method, including freeze-thaw cycling, sonication, mechanical disruption, or use of cell lysing agents.

In Vivo Peptide/Polypeptide Synthesis

The present invention also contemplates the use of nucleic acid molecules as vehicles for delivering neoantigenic peptides/polypeptides to the subject in need thereof, in vivo, in the form of, e.g., DNA/RNA vaccines (see, e.g., WO2012/159643, and WO2012/159754, hereby incorporated by reference in their entirety).

In one embodiment neoantigens may be administered to a patient in need thereof by use of a plasmid. These are plasmids which usually consist of a strong viral promoter to drive the in vivo transcription and translation of the gene (or complementary DNA) of interest (Mor, et al., (1995). The Journal of Immunology 155 (4): 2039-2046). Intron A may sometimes be included to improve mRNA stability and hence increase protein expression (Leitner et al. (1997).The Journal of Immunology 159 (12): 6112-6119). Plasmids also include a strong polyadenylation/transcriptional termination signal, such as bovine growth hormone or rabbit beta-globulin polyadenylation sequences (Alarcon et al., (1999). Adv. Parasitol. Advances in Parasitology 42: 343-410; Robinson et al., (2000). Adv. Virus Res. Advances in Virus Research 55: 1-74; Böhm et al., (1996). Journal of Immunological Methods 193 (1): 29-40.). Multicistronic vectors are sometimes constructed to express more than one immunogen, or to express an immunogen and an immunostimulatory protein (Lewis et al., (1999). Advances in Virus Research (Academic Press) 54: 129-88).

Because the plasmid is the “vehicle” from which the immunogen is expressed, optimising vector design for maximal protein expression is essential (Lewis et al., (1999). Advances in Virus Research (Academic Press) 54: 129-88). One way of enhancing protein expression is by optimising the codon usage of pathogenic mRNAs for eukaryotic cells. Another consideration is the choice of promoter. Such promoters may be the SV40 promoter or Rous Sarcoma Virus (RSV).

Plasmids may be introduced into animal tissues by a number of different methods. The two most popular approaches are injection of DNA in saline, using a standard hypodermic needle, and gene gun delivery. A schematic outline of the construction of a DNA vaccine plasmid and its subsequent delivery by these two methods into a host is illustrated at Scientific American (Weiner et al., (1999) Scientific American 281 (1): 34-41). Injection in saline is normally conducted intramuscularly (IM) in skeletal muscle, or intradermally (ID), with DNA being delivered to the extracellular spaces. This can be assisted by electroporation by temporarily damaging muscle fibres with myotoxins such as bupivacaine; or by using hypertonic solutions of saline or sucrose (Alarcon et al., (1999). Adv. Parasitol. Advances in Parasitology 42: 343-410). Immune responses to this method of delivery can be affected by many factors, including needle type, needle alignment, speed of injection, volume of injection, muscle type, and age, sex and physiological condition of the animal being injected (Alarcon et al., (1999). Adv. Parasitol. Advances in Parasitology 42: 343-410).

Gene gun delivery, the other commonly used method of delivery, ballistically accelerates plasmid DNA (pDNA) that has been adsorbed onto gold or tungsten microparticles into the target cells, using compressed helium as an accelerant (Alarcon et al., (1999). Adv. Parasitol. Advances in Parasitology 42: 343-410: Lewis et al., (1999). Advances in Virus Research (Academic Press) 54: 129-88).

Alternative delivery methods may include aerosol instillation of naked DNA on mucosal surfaces, such as the nasal and lung mucosa, (Lewis et al., (1999). Advances in Virus Research (Academic Press) 54: 129-88) and topical administration of pDNA to the eye and vaginal mucosa (Lewis et al., (1999) Advances in Virus Research (Academic Press) 54: 129-88). Mucosal surface delivery has also been achieved using cationic liposome-DNA preparations, biodegradable microspheres, attenuated Shigella or Listeria vectors for oral administration to the intestinal mucosa, and recombinant adenovirus vectors. DNA or RNA may also be delivered to cells following mild mechanical disruption of the cell membrane, temporarily permeabilizing the cells. Such a mild mechanical disruption of the membrane can be accomplished by gently forcing cells through a small aperture (Ex Vivo Cytosolic Delivery of Functional Macromolecules to Immune Cells, Sharei et al, PLOS ONE|DOI:10.1371/journal.pone.0118803 Apr. 13, 2015).

The method of delivery determines the dose of DNA required to raise an effective immune response. Saline injections require variable amounts of DNA, from 10 μg-1 mg, whereas gene gun deliveries require 100 to 1000 times less DNA than intramuscular saline injection to raise an effective immune response. Generally, 0.2 μg-20 μg are required, although quantities as low as 16 ng have been reported. These quantities vary from species to species, with mice, for example, requiring approximately 10 times less DNA than primates. Saline injections require more DNA because the DNA is delivered to the extracellular spaces of the target tissue (normally muscle), where it has to overcome physical barriers (such as the basal lamina and large amounts of connective tissue, to mention a few) before it is taken up by the cells, while gene gun deliveries bombard DNA directly into the cells, resulting in less “wastage” (See e.g., Sedegah et al., (1994). Proceedings of the National Academy of Sciences of the United States of America 91 (21): 9866-9870; Daheshia et al., (1997). The Journal of Immunology 159 (4): 1945-1952; Chen et al., (1998). The Journal of Immunology 160 (5): 2425-2432; Sizemore (1995) Science 270 (5234): 299-302; Fynan et al., (1993) Proc. Natl. Acad. Sci. U.S.A. 90 (24): 11478-82).

In one embodiment, a neoplasia vaccine or immunogenic composition may include separate DNA plasmids encoding, for example, one or more neoantigenic peptides/polypeptides as identified in according to the invention. As discussed herein, the exact choice of expression vectors can depend upon the peptide/polypeptides to be expressed, and is well within the skill of the ordinary artisan. The expected persistence of the DNA constructs (e.g., in an episomal, non-replicating, non-integrated form in the muscle cells) is expected to provide an increased duration of protection.

One or more neoantigenic peptides of the invention may be encoded and expressed in vivo using a viral based system (e.g., an adenovirus system, an adeno associated virus (AAV) vector, a poxvirus, or a lentivirus). In one embodiment, the neoplasia vaccine or immunogenic composition may include a viral based vector for use in a human patient in need thereof, such as, for example, an adenovirus (see, e.g., Baden et al. First-in-human evaluation of the safety and immunogenicity of a recombinant adenovirus serotype 26 HIV-1 Env vaccine (IPCAVD 001). J Infect Dis. 2013 Jan. 15; 207(2):240-7, hereby incorporated by reference in its entirety). Plasmids that can be used for adeno associated virus, adenovirus, and lentivirus delivery have been described previously (see e.g., U.S. Pat. Nos. 6,955,808 and 6,943,019, and U.S. Patent application No. 20080254008, hereby incorporated by reference).

The peptides and polypeptides of the invention can also be expressed by a vector, e.g., a nucleic acid molecule as herein-discussed, e.g., RNA or a DNA plasmid, a viral vector such as a poxvirus, e.g., orthopox virus, avipox virus, or adenovirus, AAV or lentivirus. This approach involves the use of a vector to express nucleotide sequences that encode the peptide of the invention. Upon introduction into an acutely or chronically infected host or into a noninfected host, the vector expresses the immunogenic peptide, and thereby elicits a host CTL response.

Among vectors that may be used in the practice of the invention, integration in the host genome of a cell is possible with retrovirus gene transfer methods, often resulting in long term expression of the inserted transgene. In a preferred embodiment the retrovirus is a lentivirus. Additionally, high transduction efficiencies have been observed in many different cell types and target tissues. The tropism of a retrovirus can be altered by incorporating foreign envelope proteins, expanding the potential target population of target cells. A retrovirus can also be engineered to allow for conditional expression of the inserted transgene, such that only certain cell types are infected by the lentivirus. Cell type specific promoters can be used to target expression in specific cell types. Lentiviral vectors are retroviral vectors (and hence both lentiviral and retroviral vectors may be used in the practice of the invention). Moreover, lentiviral vectors are preferred as they are able to transduce or infect non-dividing cells and typically produce high viral titers. Selection of a retroviral gene transfer system may therefore depend on the target tissue. Retroviral vectors are comprised of cis-acting long terminal repeats with packaging capacity for up to 6-10 kb of foreign sequence. The minimum cis-acting LTRs are sufficient for replication and packaging of the vectors, which are then used to integrate the desired nucleic acid into the target cell to provide permanent expression. Widely used retroviral vectors that may be used in the practice of the invention include those based upon murine leukemia virus (MuLV), gibbon ape leukemia virus (GaLV), Simian Immuno deficiency virus (SIV), human immuno deficiency virus (HIV), and combinations thereof (see, e.g., Buchscher et al., (1992) J. Virol. 66:2731-2739; Johann et al., (1992) J. Virol. 66:1635-1640; Sommnerfelt et al., (1990) Virol. 176:58-59; Wilson et al., (1998) J. Virol. 63:2374-2378; Miller et al., (1991) J. Virol. 65:2220-2224; PCT/US94/05700).

Also useful in the practice of the invention is a minimal non-primate lentiviral vector, such as a lentiviral vector based on the equine infectious anemia virus (EIAV) (see, e.g., Balagaan, (2006) J Gene Med; 8: 275-285, Published online 21 Nov. 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jgm.845). The vectors may have cytomegalovirus (CMV) promoter driving expression of the target gene. Accordingly, the invention contemplates amongst vector(s) useful in the practice of the invention: viral vectors, including retroviral vectors and lentiviral vectors.

Lentiviral vectors have been disclosed as in the treatment for Parkinson's Disease, see, e.g., US Patent Publication No. 20120295960 and U.S. Pat. Nos. 7,303,910 and 7,351,585. Lentiviral vectors have also been disclosed for delivery to the Brain, see, e.g., US Patent Publication Nos. US20110293571; US20040013648, US20070025970, US20090111106 and U.S. Pat. No. 7,259,015. In another embodiment lentiviral vectors are used to deliver vectors to the brain of those being treated for a disease.

As to lentivirus vector systems useful in the practice of the invention, mention is made of U.S. Pat. Nos. 6,428,953, 6,165,782, 6,013,516, 5,994,136, 6,312,682, and 7,198,784, and documents cited therein.

In an embodiment herein the delivery is via an lentivirus. Zou et al. administered about 10 μl of a recombinant lentivirus having a titer of 1×10⁹ transducing units (TU)/ml by an intrathecal catheter. These sort of dosages can be adapted or extrapolated to use of a retroviral or lentiviral vector in the present invention. For transduction in tissues such as the brain, it is necessary to use very small volumes, so the viral preparation is concentrated by ultracentrifugation. The resulting preparation should have at least 10⁸ TU/ml, preferably from 10⁸ to 10⁹ TU/ml, more preferably at least 10⁹ TU/ml. Other methods of concentration such as ultrafiltration or binding to and elution from a matrix may be used.

In other embodiments the amount of lentivirus administered may be 1.x.10⁵ or about 1.x.10⁵ plaque forming units (PFU), 5.x.10⁵ or about 5.x.10⁵ PFU, 1.x.10⁶ or about 1.x10⁶ PFU, 5.x.10⁶ or about 5.x.10⁶ PFU, 1.x.10⁷ or about 1.x.10⁷ PFU, 5.x.10⁷ or about 5.x.10⁷ PFU, 1.x.10⁸ or about 1.x.10⁸ PFU, 5.x.10⁸ or about 5.x.10⁸ PFU, 1.x.10⁹ or about 1.x.10⁹ PFU, 5.x.10⁹ or about 5.x.10⁹ PFU, 1.x.10¹⁰ or about 1.x.10¹⁰ PFU or 5.x.10¹⁰ or about 5.x.10¹⁰ PFU as total single dosage for an average human of 75 kg or adjusted for the weight and size and species of the subject. One of skill in the art can determine suitable dosage. Suitable dosages for a virus can be determined empirically.

Also useful in the practice of the invention is an adenovirus vector. One advantage is the ability of recombinant adenoviruses to efficiently transfer and express recombinant genes in a variety of mammalian cells and tissues in vitro and in vivo, resulting in the high expression of the transferred nucleic acids. Further, the ability to productively infect quiescent cells, expands the utility of recombinant adenoviral vectors. In addition, high expression levels ensure that the products of the nucleic acids will be expressed to sufficient levels to generate an immune response (see e.g., U.S. Pat. No. 7,029,848, hereby incorporated by reference).

As to adenovirus vectors useful in the practice of the invention, mention is made of U.S. Pat. No. 6,955,808. The adenovirus vector used can be selected from the group consisting of the Ad5, Ad35, Ad11, C6, and C7 vectors. The sequence of the Adenovirus 5 (“Ad5”) genome has been published. (Chroboczek, J., Bieber, F., and Jacrot, B. (1992) The Sequence of the Genome of Adenovirus Type 5 and Its Comparison with the Genome of Adenovirus Type 2, Virology 186, 280-285; the contents if which is hereby incorporated by reference). Ad35 vectors are described in U.S. Pat. Nos. 6,974,695, 6,913,922, and 6,869,794. Ad11 vectors are described in U.S. Pat. No. 6,913,922. C6 adenovirus vectors are described in U.S. Pat. Nos. 6,780,407; 6,537,594; 6,309,647; 6,265,189; 6,156,567; 6,090,393; 5,942,235 and 5,833,975. C7 vectors are described in U.S. Pat. No. 6,277,558. Adenovirus vectors that are E1-defective or deleted, E3-defective or deleted, and/or E4-defective or deleted may also be used. Certain adenoviruses having mutations in the E1 region have improved safety margin because E1-defective adenovirus mutants are replication-defective in non-permissive cells, or, at the very least, are highly attenuated. Adenoviruses having mutations in the E3 region may have enhanced the immunogenicity by disrupting the mechanism whereby adenovirus down-regulates MHC class I molecules. Adenoviruses having E4 mutations may have reduced immunogenicity of the adenovirus vector because of suppression of late gene expression. Such vectors may be particularly useful when repeated re-vaccination utilizing the same vector is desired. Adenovirus vectors that are deleted or mutated in E1, E3, E4, E1 and E3, and E1 and E4 can be used in accordance with the present invention. Furthermore, “gutless” adenovirus vectors, in which all viral genes are deleted, can also be used in accordance with the present invention. Such vectors require a helper virus for their replication and require a special human 293 cell line expressing both E1a and Cre, a condition that does not exist in natural environment. Such “gutless” vectors are non-immunogenic and thus the vectors may be inoculated multiple times for re-vaccination. The “gutless” adenovirus vectors can be used for insertion of heterologous inserts/genes such as the transgenes of the present invention, and can even be used for co-delivery of a large number of heterologous inserts/genes.

In an embodiment herein the delivery is via an adenovirus, which may be at a single booster dose containing at least 1×10⁵ particles (also referred to as particle units, pu) of adenoviral vector. In an embodiment herein, the dose preferably is at least about 1×10⁶ particles (for example, about 1×10⁶-1×10¹² particles), more preferably at least about 1×10⁷ particles, more preferably at least about 1×10⁸ particles (e.g., about 1×10⁸-1×10¹¹ particles or about 1×10⁸-1×10¹² particles), and most preferably at least about 1×10⁹ particles (e.g., about 1×10⁹-1×10¹⁰ particles or about 1×10⁹-1×10¹² particles), or even at least about 1×10¹⁰ particles (e.g., about 1×10¹⁰-1×10¹² particles) of the adenoviral vector. Alternatively, the dose comprises no more than about 1×10¹⁴ particles, preferably no more than about 1×10¹³ particles, even more preferably no more than about 1×10¹² particles, even more preferably no more than about 1×10¹¹ particles, and most preferably no more than about 1×10¹⁰ particles (e.g., no more than about 1×10⁹ articles). Thus, the dose may contain a single dose of adenoviral vector with, for example, about 1×10⁶ particle units (pu), about 2×10⁶ pu, about 4×10⁶ pu, about 1×10⁷ pu, about 2×10⁷ pu, about 4×10⁷ pu, about 1×10⁸ pu, about 2×10⁸ pu, about 4×10⁸ pu, about 1×10⁹ pu, about 2×10⁹ pu, about 4×10⁹ pu, about 1×10¹⁰ pu, about 2×10¹⁰ pu, about 4×10¹⁰ pu, about 1×10¹¹ pu, about 2×10¹¹ pu, about 4×10¹¹ pu, about 1×10¹² pu, about 2×10¹² pu, or about 4×10¹² pu of adenoviral vector. See, for example, the adenoviral vectors in U.S. Pat. No. 8,454,972 B2 to Nabel, et. al., granted on Jun. 4, 2013; incorporated by reference herein, and the dosages at col 29, lines 36-58 thereof. In an embodiment herein, the adenovirus is delivered via multiple doses.

In terms of in vivo delivery, AAV is advantageous over other viral vectors due to low toxicity and low probability of causing insertional mutagenesis because it doesn't integrate into the host genome. AAV has a packaging limit of 4.5 or 4.75 Kb. Constructs larger than 4.5 or 4.75 Kb result in significantly reduced virus production. There are many promoters that can be used to drive nucleic acid molecule expression. AAV ITR can serve as a promoter and is advantageous for eliminating the need for an additional promoter element. For ubiquitous expression, the following promoters can be used: CMV, CAG, CBh, PGK, SV40, Ferritin heavy or light chains, etc. For brain expression, the following promoters can be used: SynapsinI for all neurons, CaMKIIalpha for excitatory neurons, GAD67 or GAD65 or VGAT for GABAergic neurons, etc. Promoters used to drive RNA synthesis can include: Pol III promoters such as U6 or H1. The use of a Pol II promoter and intronic cassettes can be used to express guide RNA (gRNA).

With regard to AAV vectors useful in the practice of the invention, mention is made of U.S. Pat. Nos. 5,658,785, 7,115,391, 7,172,893, 6,953,690, 6,936,466, 6,924,128, 6,893,865, 6,793,926, 6,537,540, 6,475,769 and 6,258,595, and documents cited therein.

As to AAV, the AAV can be AAV1, AAV2, AAV5 or any combination thereof. One can select the AAV with regard to the cells to be targeted; e.g., one can select AAV serotypes 1, 2, 5 or a hybrid capsid AAV1, AAV2, AAV5 or any combination thereof for targeting brain or neuronal cells; and one can select AAV4 for targeting cardiac tissue. AAV8 is useful for delivery to the liver. The above promoters and vectors are preferred individually.

In an embodiment herein, the delivery is via an AAV. A therapeutically effective dosage for in vivo delivery of the AAV to a human is believed to be in the range of from about 20 to about 50 ml of saline solution containing from about 1×10¹⁰ to about 1×10⁵⁰ functional AAV/ml solution. The dosage may be adjusted to balance the therapeutic benefit against any side effects. In an embodiment herein, the AAV dose is generally in the range of concentrations of from about 1×10⁵ to 1×10⁵⁰ genomes AAV, from about 1×10⁸ to 1×10²⁰ genomes AAV, from about 1×10¹⁰ to about 1×10¹⁶ genomes, or about 1×10¹¹ to about 1×10¹⁶ genomes AAV. A human dosage may be about 1×10¹³ genomes AAV. Such concentrations may be delivered in from about 0.001 ml to about 100 ml, about 0.05 to about 50 ml, or about 10 to about 25 ml of a carrier solution. In a preferred embodiment, AAV is used with a titer of about 2×10¹³ viral genomes/milliliter, and each of the striatal hemispheres of a mouse receives one 500 nanoliter injection. Other effective dosages can be readily established by one of ordinary skill in the art through routine trials establishing dose response curves. See, for example, U.S. Pat. No. 8,404,658 B2 to Hajjar, et al., granted on Mar. 26, 2013, at col. 27, lines 45-60.

In another embodiment effectively activating a cellular immune response for a neoplasia vaccine or immunogenic composition can be achieved by expressing the relevant neoantigens in a vaccine or immunogenic composition in a non-pathogenic microorganism. Well-known examples of such microorganisms are Mycobacterium bovis BCG, Salmonella and Pseudomona (See, U.S. Pat. No. 6,991,797, hereby incorporated by reference in its entirety).

In another embodiment a Poxvirus is used in the neoplasia vaccine or immunogenic composition. These include orthopoxvirus, avipox, vaccinia, MVA, NYVAC, canarypox, ALVAC, fowlpox, TROVAC, etc. (see e.g., Verardi et al., Hum Vaccin Immunother. 2012 July; 8(7):961-70; and Moss, Vaccine. 2013; 31(39): 4220-4222). Poxvirus expression vectors were described in 1982 and quickly became widely used for vaccine development as well as research in numerous fields. Advantages of the vectors include simple construction, ability to accommodate large amounts of foreign DNA and high expression levels.

Information concerning poxviruses that may be used in the practice of the invention, such as Chordopoxvirinae subfamily poxviruses (poxviruses of vertebrates), for instance, orthopoxviruses and avipoxviruses, e.g., vaccinia virus (e.g., Wyeth Strain, WR Strain (e.g., ATCC® VR-1354), Copenhagen Strain, NYVAC, NYVAC.1, NYVAC.2, MVA, MVA-BN), canarypox virus (e.g., Wheatley C93 Strain, ALVAC), fowlpox virus (e.g., FP9 Strain, Webster Strain, TROVAC), dovepox, pigeonpox, quailpox, and raccoon pox, inter alia, synthetic or non-naturally occurring recombinants thereof, uses thereof, and methods for making and using such recombinants may be found in scientific and patent literature, such as:

-   -   U.S. Pat. Nos. 4,603,112, 4,769,330, 5,110,587, 5,174,993,         5,364,773, 5,762,938, 5,494,807, 5,766,597, 7,767,449,         6,780,407, 6,537,594, 6,265,189, 6,214,353, 6,130,066,         6,004,777, 5,990,091, 5,942,235, 5,833,975, 5,766,597,         5,756,101, 7,045,313, 6,780,417, 8,470,598, 8,372,622,         8,268,329, 8,268,325, 8,236,560, 8,163,293, 7,964,398,         7,964,396, 7,964,395, 7,939,086, 7,923,017, 7,897,156,         7,892,533, 7,628,980, 7,459,270, 7,445,924, 7,384,644,         7,335,364, 7,189,536, 7,097,842, 6,913,752, 6,761,893,         6,682,743, 5,770,212, 5,766,882, and 5,989,562, and     -   Panicali, D. Proc. Natl. Acad. Sci. 1982; 79; 4927-493,         Panicali D. Proc. Natl. Acad. Sci. 1983; 80(17): 5364-8,         Mackett, M. Proc. Natl. Acad. Sci. 1982; 79: 7415-7419, Smith         G L. Proc. Natl. Acad. Sci. 1983; 80(23): 7155-9, Smith G L.         Nature 1983; 302: 490-5, Sullivan V J. Gen. Vir. 1987; 68:         2587-98, Perkus M Journal of Leukocyte Biology 1995; 58:1-13,         Yilma T D. Vaccine 1989; 7: 484-485, Brochier B. Nature 1991;         354: 520-22, Wiktor, T J. Proc. Natl Acd. Sci. 1984; 81: 7194-8,         Rupprecht, C E. Proc. Natl Acd. Sci. 1986; 83: 7947-50, Poulet,         H Vaccine 2007; 25(July): 5606-12, Weyer J. Vaccine 2009;         27(November): 7198-201, Buller, R M Nature 1985; 317(6040):         813-5, Buller R M. J. Virol. 1988; 62(3):866-74, Flexner, C.         Nature 1987; 330(6145): 259-62, Shida, H. J. Virol. 1988;         62(12): 4474-80, Kotwal, G J. J. Virol. 1989; 63(2): 600-6,         Child, S J. Virology 1990; 174(2): 625-9, Mayr A. Zentralbl         Bakteriol 1978; 167(5,6): 375-9, Antoine G. Virology. 1998;         244(2): 365-96, Wyatt, L S. Virology 1998; 251(2): 334-42,         Sancho, M C. J. Virol. 2002; 76(16); 8313-34, Gallego-Gomez,         J C. J. Virol. 2003; 77(19); 10606-22), Goebel S J. Virology         1990; (a,b) 179: 247-66, Tartaglia, J. Virol. 1992; 188(1):         217-32, Najera J L. J. Virol. 2006; 80(12): 6033-47, Najera,         J L. J. Virol. 2006; 80: 6033-6047, Gomez, C E. J. Gen. Virol.         2007; 88: 2473-78, Mooij, P. Jour. Of Virol. 2008; 82:         2975-2988, Gomez, C E. Curr. Gene Ther. 2011; 11: 189-217,         Cox, W. Virology 1993; 195: 845-50, Perkus, M. Jour. Of         Leukocyte Biology 1995; 58: 1-13, Blanchard T J. J Gen Virology         1998; 79(5): 1159-67, Amara R. Science 2001; 292: 69-74, Hel,         Z., J. Immunol. 2001; 167: 7180-9, Gherardi M M. J. Virol. 2003;         77: 7048-57, Didierlaurent, A. Vaccine 2004; 22: 3395-3403,         Bissht H. Proc. Nat. Aca. Sci. 2004; 101: 6641-46, McCurdy L H.         Clin. Inf. Dis 2004; 38: 1749-53, Earl P L. Nature 2004; 428:         182-85, Chen Z. J. Virol. 2005; 79: 2678-2688, Najera J L. J.         Virol. 2006; 80(12): 6033-47, Nam J H. Acta. Virol. 2007; 51:         125-30, Antonis A F. Vaccine 2007; 25: 4818-4827, B Weyer J.         Vaccine 2007; 25: 4213-22, Ferrier-Rembert A. Vaccine 2008;         26(14): 1794-804, Corbett M. Proc. Natl. Acad. Sci. 2008;         105(6): 2046-51, Kaufman H L., J. Clin. Oncol. 2004; 22:         2122-32, Amato, R J. Clin. Cancer Res. 2008; 14(22): 7504-10,         Dreicer R. Invest New Drugs 2009; 27(4): 379-86, Kantoff P W. J.         Clin. Oncol. 2010, 28, 1099-1105, Amato R J. J. Clin. Can. Res.         2010; 16(22): 5539-47, Kim, D W. Hum. Vaccine. 2010; 6: 784-791,         Oudard, S. Cancer Immunol. Immunother. 2011; 60: 261-71, Wyatt,         L S. Aids Res. Hum. Retroviruses. 2004; 20: 645-53, Gomez, C E.         Virus Research 2004; 105: 11-22, Webster, D P. Proc. Natl. Acad.         Sci. 2005; 102: 4836-4, Huang, X. Vaccine 2007; 25: 8874-84,         Gomez, C E. Vaccine 2007a; 25: 2863-85, Esteban M. Hum. Vaccine         2009; 5: 867-871, Gomez, C E. Curr. Gene therapy 2008; 8(2):         97-120, Whelan, K T. Plos one 2009; 4(6): 5934, Scriba, T J.         Eur. Jour. Immuno. 2010; 40(1): 279-90, Corbett, M. Proc. Natl.         Acad. Sci. 2008; 105: 2046-2051, Midgley, C M. J. Gen. Virol.         2008; 89: 2992-97, Von Krempelhuber, A. Vaccine 2010; 28:         1209-16, Perreau, M. J. Of Virol. 2011; October: 9854-62,         Pantaleo, G. Curr Opin HIV-AIDS. 2010: 5: 391-396,         each of which is incorporated herein by reference.

In another embodiment the vaccinia virus is used in the neoplasia vaccine or immunogenic composition to express a neoantigen. (Rolph et al., Recombinant viruses as vaccines and immunological tools. Curr Opin Immunol 9:517-524, 1997). The recombinant vaccinia virus is able to replicate within the cytoplasm of the infected host cell and the polypeptide of interest can therefore induce an immune response. Moreover, Poxviruses have been widely used as vaccine or immunogenic composition vectors because of their ability to target encoded antigens for processing by the major histocompatibility complex class I pathway by directly infecting immune cells, in particular antigen-presenting cells, but also due to their ability to self-adjuvant.

In another embodiment ALVAC is used as a vector in a neoplasia vaccine or immunogenic composition. ALVAC is a canarypox virus that can be modified to express foreign transgenes and has been used as a method for vaccination against both prokaryotic and eukaryotic antigens (Horig H, Lee D S, Conkright W, et al. Phase I clinical trial of a recombinant canarypoxvirus (ALVAC) vaccine expressing human carcinoembryonic antigen and the B7.1 co-stimulatory molecule. Cancer Immunol Immunother 2000; 49:504-14; von Mehren M, Arlen P, Tsang K Y, et al. Pilot study of a dual gene recombinant avipox vaccine containing both carcinoembryonic antigen (CEA) and B7.1 transgenes in patients with recurrent CEA-expressing adenocarcinomas. Clin Cancer Res 2000; 6:2219-28; Musey L, Ding Y, Elizaga M, et al. HIV-1 vaccination administered intramuscularly can induce both systemic and mucosal T cell immunity in HIV-1-uninfected individuals. J Immunol 2003; 171:1094-101; Paoletti E. Applications of pox virus vectors to vaccination: an update. Proc Natl Acad Sci USA 1996; 93:11349-53; U.S. Pat. No. 7,255,862). In a phase I clinical trial, an ALVAC virus expressing the tumor antigen CEA showed an excellent safety profile and resulted in increased CEA-specific T-cell responses in selected patients; objective clinical responses, however, were not observed (Marshall J L, Hawkins M J, Tsang K Y, et al. Phase I study in cancer patients of a replication-defective avipox recombinant vaccine that expresses human carcinoembryonic antigen. J Clin Oncol 1999; 17:332-7).

In another embodiment a Modified Vaccinia Ankara (MVA) virus may be used as a viral vector for a neoantigen vaccine or immunogenic composition. MVA is a member of the Orthopoxvirus family and has been generated by about 570 serial passages on chicken embryo fibroblasts of the Ankara strain of Vaccinia virus (CVA) (for review see Mayr, A., et al., Infection 3, 6-14, 1975). As a consequence of these passages, the resulting MVA virus contains 31 kilobases less genomic information compared to CVA, and is highly host-cell restricted (Meyer, H. et al., J. Gen. Virol. 72, 1031-1038, 1991). MVA is characterized by its extreme attenuation, namely, by a diminished virulence or infectious ability, but still holds an excellent immunogenicity. When tested in a variety of animal models, MVA was proven to be avirulent, even in immuno-suppressed individuals. Moreover, MVA-BN®-HER2 is a candidate immunotherapy designed for the treatment of HER-2-positive breast cancer and is currently in clinical trials. (Mandl et al., Cancer Immunol Immunother. January 2012; 61(1): 19-29). Methods to make and use recombinant MVA has been described (e.g., see U.S. Pat. Nos. 8,309,098 and 5,185,146 hereby incorporated in its entirety).

In another embodiment the modified Copenhagen strain of vaccinia virus, NYVAC and NYVAC variations are used as a vector (see U.S. Pat. No. 7,255,862; PCT WO 95/30018; U.S. Pat. Nos. 5,364,773 and 5,494,807, hereby incorporated by reference in its entirety).

In one embodiment recombinant viral particles of the vaccine or immunogenic composition are administered to patients in need thereof. Dosages of expressed neoantigen can range from a few to a few hundred micrograms, e.g., 5 to 500 .mu.g. The vaccine or immunogenic composition can be administered in any suitable amount to achieve expression at these dosage levels. The viral particles can be administered to a patient in need thereof or transfected into cells in an amount of about at least 10^(3.5) pfu; thus, the viral particles are preferably administered to a patient in need thereof or infected or transfected into cells in at least about 10⁴ pfu to about 10⁶ pfu; however, a patient in need thereof can be administered at least about 10⁸ pfu such that a more preferred amount for administration can be at least about 10⁷ pfu to about 10⁹ pfu. Doses as to NYVAC are applicable as to ALVAC, MVA, MVA-BN, and avipoxes, such as canarypox and fowlpox.

Vaccine or Immunogenic Composition Adjuvant

Effective vaccine or immunogenic compositions advantageously include a strong adjuvant to initiate an immune response. As described herein, poly-ICLC, an agonist of TLR3 and the RNA helicase-domains of MDA5 and RIG3, has shown several desirable properties for a vaccine or immunogenic composition adjuvant. These properties include the induction of local and systemic activation of immune cells in vivo, production of stimulatory chemokines and cytokines, and stimulation of antigen-presentation by DCs. Furthermore, poly-ICLC can induce durable CD4+ and CD8+ responses in humans. Importantly, striking similarities in the upregulation of transcriptional and signal transduction pathways were seen in subjects vaccinated with poly-ICLC and in volunteers who had received the highly effective, replication-competent yellow fever vaccine. Furthermore, >90% of ovarian carcinoma patients immunized with poly-ICLC in combination with a NY-ESO-1 peptide vaccine (in addition to Montanide) showed induction of CD4+ and CD8+ T cell, as well as antibody responses to the peptide in a recent phase 1 study. At the same time, poly-ICLC has been extensively tested in more than 25 clinical trials to date and exhibited a relatively benign toxicity profile. In addition to a powerful and specific immunogen the neoantigen peptides may be combined with an adjuvant (e.g., poly-ICLC) or another anti-neoplastic agent. Without being bound by theory, these neoantigens are expected to bypass central thymic tolerance (thus allowing stronger anti-tumor T cell response), while reducing the potential for autoimmunity (e.g., by avoiding targeting of normal self-antigens). An effective immune response advantageously includes a strong adjuvant to activate the immune system (Speiser and Romero, Molecularly defined vaccines for cancer immunotherapy, and protective T cell immunity Seminars in Immunol 22:144 (2010)). For example, Toll-like receptors (TLRs) have emerged as powerful sensors of microbial and viral pathogen “danger signals”, effectively inducing the innate immune system, and in turn, the adaptive immune system (Bhardwaj and Gnjatic, TLR AGONISTS: Are They Good Adjuvants? Cancer J. 16:382-391 (2010)). Among the TLR agonists, poly-ICLC (a synthetic double-stranded RNA mimic) is one of the most potent activators of myeloid-derived dendritic cells. In a human volunteer study, poly-ICLC has been shown to be safe and to induce a gene expression profile in peripheral blood cells comparable to that induced by one of the most potent live attenuated viral vaccines, the yellow fever vaccine YF-17D (Caskey et al, Synthetic double-stranded RNA induces innate immune responses similar to a live viral vaccine in humans J Exp Med 208:2357 (2011)). In a preferred embodiment Hiltonol®, a GMP preparation of poly-ICLC prepared by Oncovir, Inc, is utilized as the adjuvant. In other embodiments, other adjuvants described herein are envisioned. For instance oil-in-water, water-in-oil or multiphasic W/O/W; see, e.g., U.S. Pat. No. 7,608,279 and Aucouturier et al, Vaccine 19 (2001), 2666-2672, and documents cited therein.

Indications

Examples of cancers and cancer conditions that can be treated with the therapy of this document include, but are not limited to a patient in need thereof that has been diagnosed as having cancer, or at risk of developing cancer. The subject may have a solid tumor such as breast, ovarian, prostate, lung, kidney, gastric, colon, testicular, head and neck, pancreas, brain, melanoma, and other tumors of tissue organs and hematological tumors, such as lymphomas and leukemias, including acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, T cell lymphocytic leukemia, and B cell lymphomas, tumors of the brain and central nervous system (e.g., tumors of the meninges, brain, spinal cord, cranial nerves and other parts of the CNS, such as glioblastomas or medulla blastomas); head and/or neck cancer, breast tumors, tumors of the circulatory system (e.g., heart, mediastinum and pleura, and other intrathoracic organs, vascular tumors, and tumor-associated vascular tissue); tumors of the blood and lymphatic system (e.g., Hodgkin's disease, Non-Hodgkin's disease lymphoma, Burkitt's lymphoma, AIDS-related lymphomas, malignant immunoproliferative diseases, multiple myeloma, and malignant plasma cell neoplasms, lymphoid leukemia, myeloid leukemia, acute or chronic lymphocytic leukemia, monocytic leukemia, other leukemias of specific cell type, leukemia of unspecified cell type, unspecified malignant neoplasms of lymphoid, hematopoietic and related tissues, such as diffuse large cell lymphoma, T-cell lymphoma or cutaneous T-cell lymphoma); tumors of the excretory system (e.g., kidney, renal pelvis, ureter, bladder, and other urinary organs); tumors of the gastrointestinal tract (e.g., esophagus, stomach, small intestine, colon, colorectal, rectosigmoid junction, rectum, anus, and anal canal); tumors involving the liver and intrahepatic bile ducts, gall bladder, and other parts of the biliary tract, pancreas, and other digestive organs; tumors of the oral cavity (e.g., lip, tongue, gum, floor of mouth, palate, parotid gland, salivary glands, tonsil, oropharynx, nasopharynx, puriform sinus, hypopharynx, and other sites of the oral cavity); tumors of the reproductive system (e.g., vulva, vagina, Cervix uteri, uterus, ovary, and other sites associated with female genital organs, placenta, penis, prostate, testis, and other sites associated with male genital organs); tumors of the respiratory tract (e.g., nasal cavity, middle ear, accessory sinuses, larynx, trachea, bronchus and lung, such as small cell lung cancer and non-small cell lung cancer); tumors of the skeletal system (e.g., bone and articular cartilage of limbs, bone articular cartilage and other sites); tumors of the skin (e.g., malignant melanoma of the skin, non-melanoma skin cancer, basal cell carcinoma of skin, squamous cell carcinoma of skin, mesothelioma, Kaposi's sarcoma); and tumors involving other tissues including peripheral nerves and autonomic nervous system, connective and soft tissue, retroperitoneoum and peritoneum, eye, thyroid, adrenal gland, and other endocrine glands and related structures, secondary and unspecified malignant neoplasms of lymph nodes, secondary malignant neoplasm of respiratory and digestive systems and secondary malignant neoplasm of other sites. Thus the population of subjects described herein may be suffering from one of the above cancer types. In other embodiments, the population of subjects may be all subjects suffering from solid tumors, or all subjects suffering from liquid tumors.

Of special interest is the treatment of Non-Hodgkin's Lymphoma (NHL), clear cell Renal Cell Carcinoma (ccRCC), metastatic melanoma, sarcoma, leukemia or a cancer of the bladder, colon, brain, breast, head and neck, endometrium, lung, ovary, pancreas or prostate. In certain embodiments, the melanoma is high risk melanoma.

Cancers that can be treated using the therapy described herein may include among others cases which are refractory to treatment with other chemotherapeutics. The term “refractory, as used herein refers to a cancer (and/or metastases thereof), which shows no or only weak antiproliferative response (e.g., no or only weak inhibition of tumor growth) after treatment with another chemotherapeutic agent. These are cancers that cannot be treated satisfactorily with other chemotherapeutics. Refractory cancers encompass not only (i) cancers where one or more chemotherapeutics have already failed during treatment of a patient, but also (ii) cancers that can be shown to be refractory by other means, e.g., biopsy and culture in the presence of chemotherapeutics.

The therapy described herein is also applicable to the treatment of patients in need thereof who have not been previously treated.

The therapy described herein is also applicable where the subject has no detectable neoplasia but is at high risk for disease recurrence.

Also of special interest is the treatment of patients in need thereof who have undergone Autologous Hematopoietic Stem Cell Transplant (AHSCT), and in particular patients who demonstrate residual disease after undergoing AHSCT. The post-AHSCT setting is characterized by a low volume of residual disease, the infusion of immune cells to a situation of homeostatic expansion, and the absence of any standard relapse-delaying therapy. These features provide a unique opportunity to use the claimed neoplastic vaccine or immunogenic composition compositions to delay disease relapse.

Pharmaceutical Compositions/Methods of Delivery

The present invention is also directed to pharmaceutical compositions comprising an effective amount of one or more neoantigenic peptides as described herein (including a pharmaceutically acceptable salt, thereof), optionally in combination with a pharmaceutically acceptable carrier, excipient or additive.

When administered as a combination, the therapeutic agents (i.e. the neoantigenic peptides) can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.

The compositions may be administered once daily, twice daily, once every two days, once every three days, once every four days, once every five days, once every six days, once every seven days, once every two weeks, once every three weeks, once every four weeks, once every two months, once every six months, or once per year. The dosing interval can be adjusted according to the needs of individual patients. For longer intervals of administration, extended release or depot formulations can be used.

The compositions of the invention can be used to treat diseases and disease conditions that are acute, and may also be used for treatment of chronic conditions. In particular, the compositions of the invention are used in methods to treat or prevent a neoplasia. In certain embodiments, the compounds of the invention are administered for time periods exceeding two weeks, three weeks, one month, two months, three months, four months, five months, six months, one year, two years, three years, four years, or five years, ten years, or fifteen years; or for example, any time period range in days, months or years in which the low end of the range is any time period between 14 days and 15 years and the upper end of the range is between 15 days and 20 years (e.g., 4 weeks and 15 years, 6 months and 20 years). In some cases, it may be advantageous for the compounds of the invention to be administered for the remainder of the patient's life. In preferred embodiments, the patient is monitored to check the progression of the disease or disorder, and the dose is adjusted accordingly. In preferred embodiments, treatment according to the invention is effective for at least two weeks, three weeks, one month, two months, three months, four months, five months, six months, one year, two years, three years, four years, or five years, ten years, fifteen years, twenty years, or for the remainder of the subject's life.

Surgical resection uses surgery to remove abnormal tissue in cancer, such as mediastinal, neurogenic, or germ cell tumors, or thymoma. In certain embodiments, administration of the composition is initiated following tumor resection. In other embodiments, administration of the neoplasia vaccine or immunogenic composition is initiated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more weeks after tumor resection. Preferably, administration of the neoplasia vaccine or immunogenic composition is initiated 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks after tumor resection.

Prime/boost regimens refer to the successive administrations of a vaccine or immunogenic or immunological compositions. In certain embodiments, administration of the neoplasia vaccine or immunogenic composition is in a prime/boost dosing regimen, for example administration of the neoplasia vaccine or immunogenic composition at weeks 1, 2, 3 or 4 as a prime and administration of the neoplasia vaccine or immunogenic composition is at months 2, 3 or 4 as a boost. In another embodiment heterologous prime-boost strategies are used to ellicit a greater cytotoxic T-cell response (see Schneider et al., Induction of CD8+ T cells using heterologous prime-boost immunisation strategies, Immunological Reviews Volume 170, Issue 1, pages 29-38, August 1999). In another embodiment DNA encoding neoantigens is used to prime followed by a protein boost. In another embodiment protein is used to prime followed by boosting with a virus encoding the neoantigen. In another embodiment a virus encoding the neoantigen is used to prime and another virus is used to boost. In another embodiment protein is used to prime and DNA is used to boost. In a preferred embodiment a DNA vaccine or immunogenic composition is used to prime a T-cell response and a recombinant viral vaccine or immunogenic composition is used to boost the response. In another preferred embodiment a viral vaccine or immunogenic composition is coadministered with a protein or DNA vaccine or immunogenic composition to act as an adjuvant for the protein or DNA vaccine or immunogenic composition. The patient can then be boosted with either the viral vaccine or immunogenic composition, protein, or DNA vaccine or immunogenic composition (see Hutchings et al., Combination of protein and viral vaccines induces potent cellular and humoral immune responses and enhanced protection from murine malaria challenge. Infect Immun. 2007 December; 75(12):5819-26. Epub 2007 Oct. 1).

The pharmaceutical compositions can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients in need thereof, including humans and other mammals.

Modifications of the neoantigenic peptides can affect the solubility, bioavailability and rate of metabolism of the peptides, thus providing control over the delivery of the active species. Solubility can be assessed by preparing the neoantigenic peptide and testing according to known methods well within the routine practitioner's skill in the art.

In certain embodiments of the pharmaceutical composition the pharmaceutically acceptable carrier comprises water. In certain embodiments, the pharmaceutically acceptable carrier further comprises dextrose. In certain embodiments, the pharmaceutically acceptable carrier further comprises dimethylsulfoxide. In certain embodiments, the pharmaceutical composition further comprises an immunomodulator or adjuvant. In certain embodiments, the immunodulator or adjuvant is selected from the group consisting of poly-ICLC, STING agonist, 1018 ISS, aluminum salts, Amplivax, AS15, BCG, CP-870,893, CpG7909, CyaA, dSLIM, GM-CSF, IC30, IC31, Imiquimod, ImuFact 1MP321, IS Patch, ISS, ISCOMATRIX, Juvlmmune, LipoVac, MF59, monophosphoryl lipid A, Montanide IMS 1312, Montanide ISA 206, Montanide ISA 50V, Montanide ISA-51, OK-432, OM-174, OM-197-MP-EC, ONTAK, PEPTEL, vector system, PLGA microparticles, resiquimod, SRL172, Virosomes and other Virus-like particles, YF-17D, VEGF trap, R848, beta-glucan, Pam3Cys, and Aquila's QS21 stimulon. In certain embodiments, the immunomodulator or adjuvant comprises poly-ICLC.

Xanthenone derivatives such as, for example, Vadimezan or AsA404 (also known as 5,6-dimethylaxanthenone-4-acetic acid (DMXAA)), may also be used as adjuvants according to embodiments of the invention. Alternatively, such derivatives may also be administered in parallel to the vaccine or immunogenic composition of the invention, for example via systemic or intratumoral delivery, to stimulate immunity at the tumor site. Without being bound by theory, it is believed that such xanthenone derivatives act by stimulating interferon (IFN) production via the stimulator of IFN gene ISTING) receptor (see e.g., Conlon et al. (2013) Mouse, but not Human STING, Binds and Signals in Response to the Vascular Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid, Journal of Immunology, 190:5216-25 and Kim et al. (2013) Anticancer Flavonoids are Mouse-Selective STING Agonists, 8:1396-1401).

The vaccine or immunological composition may also include an adjuvant compound chosen from the acrylic or methacrylic polymers and the copolymers of maleic anhydride and an alkenyl derivative. It is in particular a polymer of acrylic or methacrylic acid cross-linked with a polyalkenyl ether of a sugar or polyalcohol (carbomer), in particular cross-linked with an allyl sucrose or with allylpentaerythritol. It may also be a copolymer of maleic anhydride and ethylene cross-linked, for example, with divinyl ether (see U.S. Pat. No. 6,713,068 hereby incorporated by reference in its entirety).

In certain embodiments, the pH modifier can stabilize the adjuvant or immunomodulator as described herein.

In certain embodiments, a pharmaceutical composition comprises: one to five peptides, dimethylsulfoxide (DMSO), dextrose, water, succinate, poly I: poly C, poly-L-lysine, carboxymethylcellulose, and chloride. In certain embodiments, each of the one to five peptides is present at a concentration of 300 μg/ml. In certain embodiments, the pharmaceutical composition comprises ≤3% DMSO by volume. In certain embodiments, the pharmaceutical composition comprises 3.6-3.7% dextrose in water. In certain embodiments, the pharmaceutical composition comprises 3.6-3.7 mM succinate (e.g., as sodium succinate) or a salt thereof. In certain embodiments, the pharmaceutical composition comprises 0.5 mg/ml poly I: poly C. In certain embodiments, the pharmaceutical composition comprises 0.375 mg/ml poly-L-Lysine. In certain embodiments, the pharmaceutical composition comprises 1.25 mg/ml sodium carboxymethylcellulose. In certain embodiments, the pharmaceutical composition comprises 0.225% sodium chloride.

Pharmaceutical compositions comprise the herein-described tumor specific neoantigenic peptides in a therapeutically effective amount for treating diseases and conditions (e.g., a neoplasia/tumor), which have been described herein, optionally in combination with a pharmaceutically acceptable additive, carrier and/or excipient. One of ordinary skill in the art from this disclosure and the knowledge in the art will recognize that a therapeutically effective amount of one of more compounds according to the present invention may vary with the condition to be treated, its severity, the treatment regimen to be employed, the pharmacokinetics of the agent used, as well as the patient (animal or human) treated.

To prepare the pharmaceutical compositions according to the present invention, a therapeutically effective amount of one or more of the compounds according to the present invention is preferably intimately admixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dose. A carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., ocular, oral, topical or parenteral, including gels, creams ointments, lotions and time released implantable preparations, among numerous others. In preparing pharmaceutical compositions in oral dosage form, any of the usual pharmaceutical media may be used. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives including water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used. For solid oral preparations such as powders, tablets, capsules, and for solid preparations such as suppositories, suitable carriers and additives including starches, sugar carriers, such as dextrose, mannitol, lactose and related carriers, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used. If desired, the tablets or capsules may be enteric-coated or sustained release by standard techniques.

The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount for the desired indication, without causing serious toxic effects in the patient treated.

Oral compositions generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.

The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a dispersing agent such as alginic acid or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can contain, in addition to material herein discussed, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric agents.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil emulsion and as a bolus, etc.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets optionally may be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.

Methods of formulating such slow or controlled release compositions of pharmaceutically active ingredients, are known in the art and described in several issued US patents, some of which include, but are not limited to, U.S. Pat. Nos. 3,870,790; 4,226,859; 4,369,172; 4,842,866 and 5,705,190, the disclosures of which are incorporated herein by reference in their entireties. Coatings can be used for delivery of compounds to the intestine (see, e.g., U.S. Pat. Nos. 6,638,534, 5,541,171, 5,217,720, and 6,569,457, and references cited therein).

The active compound or pharmaceutically acceptable salt thereof may also be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose or fructose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

Solutions or suspensions used for ocular, parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose.

In certain embodiments, the pharmaceutically acceptable carrier is an aqueous solvent, i.e., a solvent comprising water, optionally with additional co-solvents. Exemplary pharmaceutically acceptable carriers include water, buffer solutions in water (such as phosphate-buffered saline (PBS), and 5% dextrose in water (D5W). In certain embodiments, the aqueous solvent further comprises dimethyl sulfoxide (DMSO), e.g., in an amount of about 1-4%, or 1-3%. In certain embodiments, the pharmaceutically acceptable carrier is isotonic (i.e., has substantially the same osmotic pressure as a body fluid such as plasma).

In one embodiment, the active compounds are prepared with carriers that protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, and polylactic-co-glycolic acid (PLGA). Methods for preparation of such formulations are within the ambit of the skilled artisan in view of this disclosure and the knowledge in the art.

A skilled artisan from this disclosure and the knowledge in the art recognizes that in addition to tablets, other dosage forms can be formulated to provide slow or controlled release of the active ingredient. Such dosage forms include, but are not limited to, capsules, granulations and gel-caps.

Liposomal suspensions may also be pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposomal formulations may be prepared by dissolving appropriate lipid(s) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound are then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension. Other methods of preparation well known by those of ordinary skill may also be used in this aspect of the present invention.

The formulations may conveniently be presented in unit dosage form and may be prepared by conventional pharmaceutical techniques. Such techniques include the step of bringing into association the active ingredient and the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

Formulations and compositions suitable for topical administration in the mouth include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the ingredient to be administered in a suitable liquid carrier.

Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising the ingredient to be administered in a pharmaceutical acceptable carrier. A preferred topical delivery system is a transdermal patch containing the ingredient to be administered.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

Formulations suitable for nasal administration, wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of 20 to 500 microns which is administered in the manner in which snuff is administered, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. If administered intravenously, preferred carriers include, for example, physiological saline or phosphate buffered saline (PBS).

For parenteral formulations, the carrier usually comprises sterile water or aqueous sodium chloride solution, though other ingredients including those which aid dispersion may be included. Of course, where sterile water is to be used and maintained as sterile, the compositions and carriers are also sterilized. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Administration of the active compound may range from continuous (intravenous drip) to several oral administrations per day (for example, Q.I.D.) and may include oral, topical, eye or ocular, parenteral, intramuscular, intravenous, sub-cutaneous, transdermal (which may include a penetration enhancement agent), buccal and suppository administration, among other routes of administration, including through an eye or ocular route.

The neoplasia vaccine or immunogenic composition, and any additional agents, may be administered by injection, orally, parenterally, by inhalation spray, rectally, vaginally, or topically in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. The term parenteral as used herein includes, into a lymph node or nodes, subcutaneous, intravenous, intramuscular, intrasternal, infusion techniques, intraperitoneally, eye or ocular, intravitreal, intrabuccal, transdermal, intranasal, into the brain, including intracranial and intradural, into the joints, including ankles, knees, hips, shoulders, elbows, wrists, directly into tumors, and the like, and in suppository form.

In certain embodiments, the vaccine or immunogenic composition is administered intravenously or subcutaneously. Various techniques can be used for providing the subject compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access. Where an organ or tissue is accessible because of removal from the patient, such organ or tissue may be bathed in a medium containing the subject compositions, the subject compositions may be painted onto the organ, or may be applied in any convenient way.

The tumor specific neoantigenic peptides may be administered through a device suitable for the controlled and sustained release of a composition effective in obtaining a desired local or systemic physiological or pharmacological effect. The method includes positioning the sustained released drug delivery system at an area wherein release of the agent is desired and allowing the agent to pass through the device to the desired area of treatment.

The tumor specific neoantigenic peptides may be utilized in combination with at least one known other therapeutic agent, or a pharmaceutically acceptable salt of said agent. Examples of known therapeutic agents which can be used for combination therapy include, but are not limited to, corticosteroids (e.g., cortisone, prednisone, dexamethasone), non-steroidal anti-inflammatory drugs (NSAIDS) (e.g., ibuprofen, celecoxib, aspirin, indomethicin, naproxen), alkylating agents such as busulfan, cis-platin, mitomycin C, and carboplatin; antimitotic agents such as colchicine, vinblastine, paclitaxel, and docetaxel; topo I inhibitors such as camptothecin and topotecan; topo II inhibitors such as doxorubicin and etoposide; and/or RNA/DNA antimetabolites such as 5-azacytidine, 5-fluorouracil and methotrexate; DNA antimetabolites such as 5-fluoro-2′-deoxy-uridine, ara-C, hydroxyurea and thioguanine; antibodies such as HERCEPTIN and RITUXAN.

It should be understood that in addition to the ingredients particularly mentioned herein, the formulations of the present invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents.

Pharmaceutically acceptable salt forms may be the preferred chemical form of compounds according to the present invention for inclusion in pharmaceutical compositions according to the present invention.

The present compounds or their derivatives, including prodrug forms of these agents, can be provided in the form of pharmaceutically acceptable salts. As used herein, the term pharmaceutically acceptable salts or complexes refers to appropriate salts or complexes of the active compounds according to the present invention which retain the desired biological activity of the parent compound and exhibit limited toxicological effects to normal cells. Nonlimiting examples of such salts are (a) acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, and polyglutamic acid, among others; (b) base addition salts formed with metal cations such as zinc, calcium, sodium, potassium, and the like, among numerous others.

The compounds herein are commercially available or can be synthesized. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formulae herein is evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, 2nd. Ed., Wiley-VCH Publishers (1999); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.

The additional agents that may be included with the tumor specific neo-antigenic peptides of this invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention. The compounds of this invention may also be represented in multiple tautomeric forms, in such instances, the invention expressly includes all tautomeric forms of the compounds described herein (e.g., alkylation of a ring system may result in alkylation at multiple sites, the invention expressly includes all such reaction products). All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.

Dosage

When the agents described herein are administered as pharmaceuticals to humans or animals, they can be given per se or as a pharmaceutical composition containing active ingredient in combination with a pharmaceutically acceptable carrier, excipient, or diluent.

Actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the invention can be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. Generally, agents or pharmaceutical compositions of the invention are administered in an amount sufficient to reduce or eliminate symptoms associated with neoplasia, e.g. cancer or tumors.

A preferred dose of an agent is the maximum that a patient can tolerate and not develop serious or unacceptable side effects. Exemplary dose ranges include 0.01 mg to 250 mg per day, 0.01 mg to 100 mg per day, 1 mg to 100 mg per day, 10 mg to 100 mg per day, 1 mg to 10 mg per day, and 0.01 mg to 10 mg per day. A preferred dose of an agent is the maximum that a patient can tolerate and not develop serious or unacceptable side effects. In embodiments, the agent is administered at a concentration of about 10 micrograms to about 100 mg per kilogram of body weight per day, about 0.1 to about 10 mg/kg per day, or about 1.0 mg to about 10 mg/kg of body weight per day.

In embodiments, the pharmaceutical composition comprises an agent in an amount ranging between 1 and 10 mg, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg.

In embodiments, the therapeutically effective dosage produces a serum concentration of an agent of from about 0.1 ng/ml to about 50-100 mg/ml. The pharmaceutical compositions 5 typically should provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day. For example, dosages for systemic administration to a human patient can range from 1-10 mg/kg, 20-80 mg/kg, 5-50 mg/kg, 75-150 mg/kg, 100-500 mg/kg, 250-750 mg/kg, 500-1000 mg/kg, 1-10 mg/kg, 5-50 mg/kg, 25-75 mg/kg, 50-100 mg/kg, 100-250 mg/kg, 50-100 mg/kg, 250-500 mg/kg, 500-750 mg/kg, 750-1000 mg/kg, 1000-1500 mg/kg, 10 1500-2000 mg/kg, 5 mg/kg, 20 mg/kg, 50 mg/kg, 100 mg/kg, 500 mg/kg, 1000 mg/kg, 1500 mg/kg, or 2000 mg/kg. Pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 5000 mg, for example from about 100 to about 2500 mg of the compound or a combination of essential ingredients per dosage unit form.

In embodiments, about 50 nM to about 1 μM of an agent is administered to a subject. In related embodiments, about 50-100 nM, 50-250 nM, 100-500 nM, 250-500 nM, 250-750 nM, 500-750 nM, 500 nM to 1 μM, or 750 nM to 1 μM of an agent is administered to a subject.

Determination of an effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, an efficacious or effective amount of an agent is determined by first administering a low dose of the agent(s) and then incrementally increasing the administered dose or dosages until a desired effect (e.g., reduce or eliminate symptoms associated with viral infection or autoimmune disease) is observed in the treated subject, with minimal or acceptable toxic side effects. Applicable methods for determining an appropriate dose and dosing schedule for administration of a pharmaceutical composition of the present invention are described, for example, in Goodman and Gilman's The Pharmacological Basis of Therapeutics, Goodman et al., eds., 11th Edition, McGraw-Hill 2005, and Remington: The Science and Practice of Pharmacy, 20th and 21st Editions, Gennaro and University of the Sciences in Philadelphia, Eds., Lippencott Williams & Wilkins (2003 and 2005), each of which is hereby incorporated by reference.

Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as herein discussed, or an appropriate fraction thereof, of the administered ingredient.

The dosage regimen for treating a disorder or a disease with the tumor specific neoantigenic peptides of this invention and/or compositions of this invention is based on a variety of factors, including the type of disease, the age, weight, sex, medical condition of the patient, the severity of the condition, the route of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods.

The amounts and dosage regimens administered to a subject can depend on a number of factors, such as the mode of administration, the nature of the condition being treated, the body weight of the subject being treated and the judgment of the prescribing physician; all such factors being within the ambit of the skilled artisan from this disclosure and the knowledge in the art.

The amount of compound included within therapeutically active formulations according to the present invention is an effective amount for treating the disease or condition. In general, a therapeutically effective amount of the present preferred compound in dosage form usually ranges from slightly less than about 0.025 mg/kg/day to about 2.5 g/kg/day, preferably about 0.1 mg/kg/day to about 100 mg/kg/day of the patient or considerably more, depending upon the compound used, the condition or infection treated and the route of administration, although exceptions to this dosage range may be contemplated by the present invention. In its most preferred form, compounds according to the present invention are administered in amounts ranging from about 1 mg/kg/day to about 100 mg/kg/day. The dosage of the compound can depend on the condition being treated, the particular compound, and other clinical factors such as weight and condition of the patient and the route of administration of the compound. It is to be understood that the present invention has application for both human and veterinary use.

For oral administration to humans, a dosage of between approximately 0.1 to 100 mg/kg/day, preferably between approximately 1 and 100 mg/kg/day, is generally sufficient.

Where drug delivery is systemic rather than topical, this dosage range generally produces effective blood level concentrations of active compound ranging from less than about 0.04 to about 400 micrograms/cc or more of blood in the patient. The compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing 0.001 to 3000 mg, preferably 0.05 to 500 mg of active ingredient per unit dosage form. An oral dosage of 10-250 mg is usually convenient.

According to certain exemplary embodiments, the vaccine or immunogenic composition is administered at a dose of about 10 μg to 1 mg per neoantigenic peptide. According to certain exemplary embodiments, the vaccine or immunogenic composition is administered at an average weekly dose level of about 10 μg to 2000 μg per neoantigenic peptide.

The concentration of active compound in the drug composition will depend on absorption, distribution, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.

The invention provides for pharmaceutical compositions containing at least one tumor specific neoantigen described herein. In embodiments, the pharmaceutical compositions contain a pharmaceutically acceptable carrier, excipient, or diluent, which includes any pharmaceutical agent that does not itself induce the production of an immune response harmful to a subject receiving the composition, and which may be administered without undue toxicity. As used herein, the term “pharmaceutically acceptable” means being approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopia, European Pharmacopia or other generally recognized pharmacopia for use in mammals, and more particularly in humans. These compositions can be useful for treating and/or preventing viral infection and/or autoimmune disease.

A thorough discussion of pharmaceutically acceptable carriers, diluents, and other excipients is presented in Remington's Pharmaceutical Sciences (17th ed., Mack Publishing Company) and Remington: The Science and Practice of Pharmacy (21st ed., Lippincott Williams & Wilkins), which are hereby incorporated by reference. The formulation of the pharmaceutical composition should suit the mode of administration. In embodiments, the pharmaceutical composition is suitable for administration to humans, and can be sterile, non-particulate and/or non-pyrogenic.

Pharmaceutically acceptable carriers, excipients, or diluents include, but are not limited, to saline, buffered saline, dextrose, water, glycerol, ethanol, sterile isotonic aqueous buffer, and combinations thereof.

Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives, and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include, but are not limited to: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

In embodiments, the pharmaceutical composition is provided in a solid form, such as a lyophilized powder suitable for reconstitution, a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.

In embodiments, the pharmaceutical composition is supplied in liquid form, for example, in a sealed container indicating the quantity and concentration of the active ingredient in the pharmaceutical composition. In related embodiments, the liquid form of the pharmaceutical composition is supplied in a hermetically sealed container.

Methods for formulating the pharmaceutical compositions of the present invention are conventional and well known in the art (see Remington and Remington's). One of skill in the art can readily formulate a pharmaceutical composition having the desired characteristics (e.g., route of administration, biosafety, and release profile).

Methods for preparing the pharmaceutical compositions include the step of bringing into association the active ingredient with a pharmaceutically acceptable carrier and, optionally, one or more accessory ingredients. The pharmaceutical compositions can be prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. Additional methodology for preparing the pharmaceutical compositions, including the preparation of multilayer dosage forms, are described in Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (9th ed., Lippincott Williams & Wilkins), which is hereby incorporated by reference.

Pharmaceutical compositions suitable for oral administration can be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound(s) described herein, a derivative thereof, or a pharmaceutically acceptable salt or prodrug thereof as the active ingredient(s). The active ingredient can also be administered as a bolus, electuary, or paste.

In solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, excipients, or diluents, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical compositions can also comprise buffering agents. Solid compositions of a similar type can also be prepared using fillers in soft and hard-filled gelatin capsules, and excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (for example, gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrants (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-actives, and/or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.

The tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art.

In some embodiments, in order to prolong the effect of an active ingredient, it is desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the active ingredient then depends upon its rate of dissolution which, in turn, can depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered active ingredient is accomplished by dissolving or suspending the compound in an oil vehicle. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

Controlled release parenteral compositions can be in form of aqueous suspensions, microspheres, microcapsules, magnetic microspheres, oil solutions, oil suspensions, emulsions, or the active ingredient can be incorporated in biocompatible carrier(s), liposomes, nanoparticles, implants or infusion devices.

Materials for use in the preparation of microspheres and/or microcapsules include biodegradable/bioerodible polymers such as polyglactin, poly-(isobutyl cyanoacrylate), poly(2-hydroxyethyl-L-glutamine) and poly(lactic acid).

Biocompatible carriers which can be used when formulating a controlled release parenteral formulation include carbohydrates such as dextrans, proteins such as albumin, lipoproteins or antibodies.

Materials for use in implants can be non-biodegradable, e.g., polydimethylsiloxane, or biodegradable such as, e.g., poly(caprolactone), poly(lactic acid), poly(glycolic acid) or poly(ortho esters).

In embodiments, the active ingredient(s) are administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation, or solid particles containing the compound. A nonaqueous (e.g., fluorocarbon propellant) suspension can be used. The pharmaceutical composition can also be administered using a sonic nebulizer, which would minimize exposing the agent to shear, which can result in degradation of the compound.

Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of the active ingredient(s) together with conventional pharmaceutically-acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

Dosage forms for topical or transdermal administration of an active ingredient(s) includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active ingredient(s) can be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants as appropriate.

Transdermal patches suitable for use in the present invention are disclosed in Transdermal Drug Delivery: Developmental Issues and Research Initiatives (Marcel Dekker Inc., 1989) and U.S. Pat. Nos. 4,743,249, 4,906,169, 5,198,223, 4,816,540, 5,422,119, 5,023,084, which are hereby incorporated by reference. The transdermal patch can also be any transdermal patch well known in the art, including transscrotal patches. Pharmaceutical compositions in such transdermal patches can contain one or more absorption enhancers or skin permeation enhancers well known in the art (see, e.g., U.S. Pat. Nos. 4,379,454 and 4,973,468, which are hereby incorporated by reference). Transdermal therapeutic systems for use in the present invention can be based on iontophoresis, diffusion, or a combination of these two effects.

Transdermal patches have the added advantage of providing controlled delivery of active ingredient(s) to the body. Such dosage forms can be made by dissolving or dispersing the active ingredient(s) in a proper medium. Absorption enhancers can also be used to increase the flux of the active ingredient across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active ingredient(s) in a polymer matrix or gel.

Such pharmaceutical compositions can be in the form of creams, ointments, lotions, liniments, gels, hydrogels, solutions, suspensions, sticks, sprays, pastes, plasters and other kinds of transdermal drug delivery systems. The compositions can also include pharmaceutically acceptable carriers or excipients such as emulsifying agents, antioxidants, buffering agents, preservatives, humectants, penetration enhancers, chelating agents, gel-forming agents, ointment bases, perfumes, and skin protective agents.

Examples of emulsifying agents include, but are not limited to, naturally occurring gums, e.g. gum acacia or gum tragacanth, naturally occurring phosphatides, e.g. soybean lecithin and sorbitan monooleate derivatives.

Examples of antioxidants include, but are not limited to, butylated hydroxy anisole (BHA), ascorbic acid and derivatives thereof, tocopherol and derivatives thereof, and cysteine.

Examples of preservatives include, but are not limited to, parabens, such as methyl or propyl p-hydroxybenzoate and benzalkonium chloride.

Examples of humectants include, but are not limited to, glycerin, propylene glycol, sorbitol and urea.

Examples of penetration enhancers include, but are not limited to, propylene glycol, DMSO, triethanolamine, N,N-dimethylacetamide, N,N-dimethylformamide, 2-pyrrolidone and derivatives thereof, tetrahydrofurfuryl alcohol, propylene glycol, diethylene glycol monoethyl or monomethyl ether with propylene glycol monolaurate or methyl laurate, eucalyptol, lecithin, TRANSCUTOL, and AZONE.

Examples of chelating agents include, but are not limited to, sodium EDTA, citric acid and phosphoric acid.

Examples of gel forming agents include, but are not limited to, Carbopol, cellulose derivatives, bentonite, alginates, gelatin and polyvinylpyrrolidone.

In addition to the active ingredient(s), the ointments, pastes, creams, and gels of the present invention can contain excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

Injectable depot forms are made by forming microencapsule matrices of compound(s) of the invention in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer, and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.

Subcutaneous implants are well known in the art and are suitable for use in the present invention. Subcutaneous implantation methods are preferably non-irritating and mechanically resilient. The implants can be of matrix type, of reservoir type, or hybrids thereof. In matrix type devices, the carrier material can be porous or non-porous, solid or semi-solid, and permeable or impermeable to the active compound or compounds. The carrier material can be biodegradable or may slowly erode after administration. In some instances, the matrix is non-degradable but instead relies on the diffusion of the active compound through the matrix for the carrier material to degrade. Alternative subcutaneous implant methods utilize reservoir devices where the active compound or compounds are surrounded by a rate controlling membrane, e.g., a membrane independent of component concentration (possessing zero-order kinetics). Devices consisting of a matrix surrounded by a rate controlling membrane also suitable for use.

Both reservoir and matrix type devices can contain materials such as polydimethylsiloxane, such as SILASTIC, or other silicone rubbers. Matrix materials can be insoluble polypropylene, polyethylene, polyvinyl chloride, ethylvinyl acetate, polystyrene and polymethacrylate, as well as glycerol esters of the glycerol palmitostearate, glycerol stearate, and glycerol behenate type. Materials can be hydrophobic or hydrophilic polymers and optionally contain solubilizing agents.

Subcutaneous implant devices can be slow-release capsules made with any suitable polymer, e.g., as described in U.S. Pat. Nos. 5,035,891 and 4,210,644, which are hereby incorporated by reference.

In general, at least four different approaches are applicable in order to provide rate control over the release and transdermal permeation of a drug compound. These approaches are: membrane-moderated systems, adhesive diffusion-controlled systems, matrix dispersion-type systems and microreservoir systems. It is appreciated that a controlled release percutaneous and/or topical composition can be obtained by using a suitable mixture of these approaches.

In a membrane-moderated system, the active ingredient is present in a reservoir which is totally encapsulated in a shallow compartment molded from a drug-impermeable laminate, such as a metallic plastic laminate, and a rate-controlling polymeric membrane such as a microporous or a non-porous polymeric membrane, e.g., ethylene-vinyl acetate copolymer. The active ingredient is released through the rate controlling polymeric membrane. In the drug reservoir, the active ingredient can either be dispersed in a solid polymer matrix or suspended in an unleachable, viscous liquid medium such as silicone fluid. On the external surface of the polymeric membrane, a thin layer of an adhesive polymer is applied to achieve an intimate contact of the transdermal system with the skin surface. The adhesive polymer is preferably a polymer which is hypoallergenic and compatible with the active drug substance.

In an adhesive diffusion-controlled system, a reservoir of the active ingredient is formed by directly dispersing the active ingredient in an adhesive polymer and then by, e.g., solvent casting, spreading the adhesive containing the active ingredient onto a flat sheet of substantially drug-impermeable metallic plastic backing to form a thin drug reservoir layer.

A matrix dispersion-type system is characterized in that a reservoir of the active ingredient is formed by substantially homogeneously dispersing the active ingredient in a hydrophilic or lipophilic polymer matrix. The drug-containing polymer is then molded into disc with a substantially well-defined surface area and controlled thickness. The adhesive polymer is spread along the circumference to form a strip of adhesive around the disc.

A microreservoir system can be considered as a combination of the reservoir and matrix dispersion type systems. In this case, the reservoir of the active substance is formed by first suspending the drug solids in an aqueous solution of water-soluble polymer and then dispersing the drug suspension in a lipophilic polymer to form a multiplicity of unleachable, microscopic spheres of drug reservoirs.

Any of the herein-described controlled release, extended release, and sustained release compositions can be formulated to release the active ingredient in about 30 minutes to about 1 week, in about 30 minutes to about 72 hours, in about 30 minutes to 24 hours, in about 30 minutes to 12 hours, in about 30 minutes to 6 hours, in about 30 minutes to 4 hours, and in about 3 hours to 10 hours. In embodiments, an effective concentration of the active ingredient(s) is sustained in a subject for 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 24 hours, 48 hours, 72 hours, or more after administration of the pharmaceutical compositions to the subject.

Vaccine or Immunogenic Compositions

The present invention is directed in some aspects to pharmaceutical compositions suitable for the prevention or treatment of cancer. In one embodiment, the composition comprises at least an immunogenic composition, e.g., a neoplasia vaccine or immunogenic composition capable of raising a specific T-cell response. The neoplasia vaccine or immunogenic composition comprises neoantigenic peptides and/or neoantigenic polypeptides corresponding to tumor specific neoantigens as described herein.

A suitable neoplasia vaccine or immunogenic composition can preferably contain a plurality of tumor specific neoantigenic peptides. In an embodiment, the vaccine or immunogenic composition can include between 1 and 100 sets of peptides, more preferably between 1 and 50 such peptides, even more preferably between 10 and 30 sets peptides, even more preferably between 15 and 25 peptides. According to another preferred embodiment, the vaccine or immunogenic composition can include at least one peptides, more preferably 2, 3, 4, or 5 peptides, In certain embodiments, the vaccine or immunogenic composition can comprise 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 different peptides.

The optimum amount of each peptide to be included in the vaccine or immunogenic composition and the optimum dosing regimen can be determined by one skilled in the art without undue experimentation. For example, the peptide or its variant may be prepared for intravenous (i.v.) injection, sub-cutaneous (s.c.) injection, intradermal (i.d.) injection, intraperitoneal (i.p.) injection, intramuscular (i.m.) injection. Preferred methods of peptide injection include s.c, i.d., i.p., i.m., and i.v. Preferred methods of DNA injection include i.d., i.m., s.c, i.p. and i.v. For example, doses of between 1 and 500 mg 50 μg and 1.5 mg, preferably 10 μg to 500 μg, of peptide or DNA may be given and can depend from the respective peptide or DNA. Doses of this range were successfully used in previous trials (Brunsvig P F, et al., Cancer Immunol Immunother. 2006; 55(12): 1553-1564; M. Staehler, et al., ASCO meeting 2007; Abstract No 3017). Other methods of administration of the vaccine or immunogenic composition are known to those skilled in the art.

In one embodiment of the present invention the different tumor specific neoantigenic peptides and/or polypeptides are selected for use in the neoplasia vaccine or immunogenic composition so as to maximize the likelihood of generating an immune attack against the neoplasias/tumors in a high proportion of subjects in the population. Without being bound by theory, it is believed that the inclusion of a diversity of tumor specific neoantigenic peptides can generate a broad scale immune attack against a neoplasia/tumor. In one embodiment, the selected tumor specific neoantigenic peptides/polypeptides are encoded by missense mutations. In a second embodiment, the selected tumor specific neoantigenic peptides/polypeptides are encoded by a combination of missense mutations and neoORF mutations. In a third embodiment, the selected tumor specific neoantigenic peptides/polypeptides are encoded by neoORF mutations.

In one embodiment in which the selected tumor specific neoantigenic peptides/polypeptides are encoded by missense mutations, the peptides and/or polypeptides are chosen based on their capability to associate with the MHC molecules of a high proportion of subjects in the population. Peptides/polypeptides derived from neoORF mutations can also be selected on the basis of their capability to associate with the MHC molecules of the patient population.

The vaccine or immunogenic composition is capable of raising a specific cytotoxic T-cells response and/or a specific helper T-cell response.

The vaccine or immunogenic composition can further comprise an adjuvant and/or a carrier. Examples of useful adjuvants and carriers are given herein. The peptides and/or polypeptides in the composition can be associated with a carrier such as, e.g., a protein or an antigen-presenting cell such as e.g. a dendritic cell (DC) capable of presenting the peptide to a T-cell.

Adjuvants are any substance whose admixture into the vaccine or immunogenic composition increases or otherwise modifies the immune response to the mutant peptide. Carriers are scaffold structures, for example a polypeptide or a polysaccharide, to which the neoantigenic peptides, is capable of being associated. Optionally, adjuvants are conjugated covalently or non-covalently to the peptides or polypeptides of the invention.

The ability of an adjuvant to increase the immune response to an antigen is typically manifested by a significant increase in immune-mediated reaction, or reduction in disease symptoms. For example, an increase in humoral immunity is typically manifested by a significant increase in the titer of antibodies raised to the antigen, and an increase in T-cell activity is typically manifested in increased cell proliferation, or cellular cytotoxicity, or cytokine secretion. An adjuvant may also alter an immune response, for example, by changing a primarily humoral or Th2 response into a primarily cellular, or Th1 response.

Suitable adjuvants include, but are not limited to 1018 ISS, aluminum salts, Amplivax, AS15, BCG, CP-870,893, CpG7909, CyaA, dSLIM, GM-CSF, IC30, IC31, Imiquimod, ImuFact 1MP321, IS Patch, ISS, ISCOMATRIX, Juvlmmune, LipoVac, MF59, monophosphoryl lipid A, Montanide IMS 1312, Montanide ISA 206, Montanide ISA 50V, Montanide ISA-51, OK-432, OM-174, OM-197-MP-EC, ONTAK, PEPTEL. vector system, PLG microparticles, resiquimod, SRL172, Virosomes and other Virus-like particles, YF-17D, VEGF trap, R848, beta-glucan, Pam3Cys, Aquila's QS21 stimulon (Aquila Biotech, Worcester, Mass., USA) which is derived from saponin, mycobacterial extracts and synthetic bacterial cell wall mimics, and other proprietary adjuvants such as Ribi's Detox. Quil or Superfos. Several immunological adjuvants (e.g., MF59) specific for dendritic cells and their preparation have been described previously (Dupuis M, et al., Cell Immunol. 1998; 186(1): 18-27; Allison A C; Dev Biol Stand. 1998; 92:3-11). Also cytokines may be used. Several cytokines have been directly linked to influencing dendritic cell migration to lymphoid tissues (e.g., TNF-alpha), accelerating the maturation of dendritic cells into efficient antigen-presenting cells for T-lymphocytes (e.g., GM-CSF, IL-1 and IL-4) (U.S. Pat. No. 5,849,589, specifically incorporated herein by reference in its entirety) and acting as immunoadjuvants (e.g., IL-12) (Gabrilovich D I, et al., J Immunother Emphasis Tumor Immunol. 1996 (6):414-418).

Toll like receptors (TLRs) may also be used as adjuvants, and are important members of the family of pattern recognition receptors (PRRs) which recognize conserved motifs shared by many micro-organisms, termed “pathogen-associated molecular patterns” (PAMPS). Recognition of these “danger signals” activates multiple elements of the innate and adaptive immune system. TLRs are expressed by cells of the innate and adaptive immune systems such as dendritic cells (DCs), macrophages, T and B cells, mast cells, and granulocytes and are localized in different cellular compartments, such as the plasma membrane, lysosomes, endosomes, and endolysosomes. Different TLRs recognize distinct PAMPS. For example, TLR4 is activated by LPS contained in bacterial cell walls, TLR9 is activated by unmethylated bacterial or viral CpG DNA, and TLR3 is activated by double stranded RNA. TLR ligand binding leads to the activation of one or more intracellular signaling pathways, ultimately resulting in the production of many key molecules associated with inflammation and immunity (particularly the transcription factor NF-κB and the Type-I interferons). TLR mediated DC activation leads to enhanced DC activation, phagocytosis, upregulation of activation and co-stimulation markers such as CD80, CD83, and CD86, expression of CCR7 allowing migration of DC to draining lymph nodes and facilitating antigen presentation to T cells, as well as increased secretion of cytokines such as type I interferons, IL-12, and IL-6. All of these downstream events are critical for the induction of an adaptive immune response.

Among the most promising cancer vaccine or immunogenic composition adjuvants currently in clinical development are the TLR9 agonist CpG and the synthetic double-stranded RNA (dsRNA) TLR3 ligand poly-ICLC. In preclinical studies poly-ICLC appears to be the most potent TLR adjuvant when compared to LPS and CpG due to its induction of pro-inflammatory cytokines and lack of stimulation of IL-10, as well as maintenance of high levels of co-stimulatory molecules in DCs1. Furthermore, poly-ICLC was recently directly compared to CpG in non-human primates (rhesus macaques) as adjuvant for a protein vaccine or immunogenic composition consisting of human papillomavirus (HPV)16 capsomers (Stahl-Hennig C, Eisenblatter M, Jasny E, et al. Synthetic double-stranded RNAs are adjuvants for the induction of T helper 1 and humoral immune responses to human papillomavirus in rhesus macaques. PLoS pathogens. April 2009; 5(4)).

CpG immuno stimulatory oligonucleotides have also been reported to enhance the effects of adjuvants in a vaccine or immunogenic composition setting. Without being bound by theory, CpG oligonucleotides act by activating the innate (non-adaptive) immune system via Toll-like receptors (TLR), mainly TLR9. CpG triggered TLR9 activation enhances antigen-specific humoral and cellular responses to a wide variety of antigens, including peptide or protein antigens, live or killed viruses, dendritic cell vaccines, autologous cellular vaccines and polysaccharide conjugates in both prophylactic and therapeutic vaccines. More importantly, it enhances dendritic cell maturation and differentiation, resulting in enhanced activation of Th1 cells and strong cytotoxic T-lymphocyte (CTL) generation, even in the absence of CD4 T-cell help. The Th1 bias induced by TLR9 stimulation is maintained even in the presence of vaccine adjuvants such as alum or incomplete Freund's adjuvant (IFA) that normally promote a Th2 bias. CpG oligonucleotides show even greater adjuvant activity when formulated or co-administered with other adjuvants or in formulations such as microparticles, nano particles, lipid emulsions or similar formulations, which are especially necessary for inducing a strong response when the antigen is relatively weak. They also accelerate the immune response and enabled the antigen doses to be reduced by approximately two orders of magnitude, with comparable antibody responses to the full-dose vaccine without CpG in some experiments (Arthur M. Krieg, Nature Reviews, Drug Discovery, 5, June 2006, 471-484). U.S. Pat. No. 6,406,705 B1 describes the combined use of CpG oligonucleotides, non-nucleic acid adjuvants and an antigen to induce an antigen-specific immune response. A commercially available CpG TLR9 antagonist is dSLIM (double Stem Loop Immunomodulator) by Mologen (Berlin, GERMANY), which is a preferred component of the pharmaceutical composition of the present invention. Other TLR binding molecules such as RNA binding TLR 7, TLR 8 and/or TLR 9 may also be used.

Other examples of useful adjuvants include, but are not limited to, chemically modified CpGs (e.g. CpR, Idera), Poly(I:C)(e.g. polyi:CI2U), non-CpG bacterial DNA or RNA as well as immunoactive small molecules and antibodies such as cyclophosphamide, sunitinib, bevacizumab, celebrex, NCX-4016, sildenafil, tadalafil, vardenafil, sorafinib, XL-999, CP-547632, pazopanib, ZD2171, AZD2171, ipilimumab, tremelimumab, and SC58175, which may act therapeutically and/or as an adjuvant. The amounts and concentrations of adjuvants and additives useful in the context of the present invention can readily be determined by the skilled artisan without undue experimentation. Additional adjuvants include colony-stimulating factors, such as Granulocyte Macrophage Colony Stimulating Factor (GM-CSF, sargramostim).

Poly-ICLC is a synthetically prepared double-stranded RNA consisting of polyI and polyC strands of average length of about 5000 nucleotides, which has been stabilized to thermal denaturation and hydrolysis by serum nucleases by the addition of polylysine and carboxymethylcellulose. The compound activates TLR3 and the RNA helicase-domain of MDA5, both members of the PAMP family, leading to DC and natural killer (NK) cell activation and production of a “natural mix” of type I interferons, cytokines, and chemokines. Furthermore, poly-ICLC exerts a more direct, broad host-targeted anti-infectious and possibly antitumor effect mediated by the two IFN-inducible nuclear enzyme systems, the 2′5′-OAS and the P1/eIF2a kinase, also known as the PKR (4-6), as well as RIG-I helicase and MDA5.

In rodents and non-human primates, poly-ICLC was shown to enhance T cell responses to viral antigens, cross-priming, and the induction of tumor-, virus-, and autoantigen-specific CD8+ T-cells. In a recent study in non-human primates, poly-ICLC was found to be essential for the generation of antibody responses and T-cell immunity to DC targeted or non-targeted HIV Gag p24 protein, emphasizing its effectiveness as a vaccine adjuvant.

In human subjects, transcriptional analysis of serial whole blood samples revealed similar gene expression profiles among the 8 healthy human volunteers receiving one single s.c. administration of poly-ICLC and differential expression of up to 212 genes between these 8 subjects versus 4 subjects receiving placebo. Remarkably, comparison of the poly-ICLC gene expression data to previous data from volunteers immunized with the highly effective yellow fever vaccine YF 17D showed that a large number of transcriptional and signal transduction canonical pathways, including those of the innate immune system, were similarly upregulated at peak time points.

More recently, an immunologic analysis was reported on patients with ovarian, fallopian tube, and primary peritoneal cancer in second or third complete clinical remission who were treated on a phase 1 study of subcutaneous vaccination with synthetic overlapping long peptides (OLP) from the cancer testis antigen NY-ESO-1 alone or with Montanide-ISA-51, or with 1.4 mg poly-ICLC and Montanide. The generation of NY-ESO-1-specific CD4+ and CD8+ T-cell and antibody responses were markedly enhanced with the addition of poly-ICLC and Montanide compared to OLP alone or OLP and Montanide.

A vaccine or immunogenic composition according to the present invention may comprise more than one different adjuvant. Furthermore, the invention encompasses a therapeutic composition comprising any adjuvant substance including any of those herein discussed. It is also contemplated that the peptide or polypeptide, and the adjuvant can be administered separately in any appropriate sequence.

A carrier may be present independently of an adjuvant. The carrier may be covalently linked to the antigen. A carrier can also be added to the antigen by inserting DNA encoding the carrier in frame with DNA encoding the antigen. The function of a carrier can for example be to confer stability, to increase the biological activity, or to increase serum half-life. Extension of the half-life can help to reduce the number of applications and to lower doses, thus are beneficial for therapeutic but also economic reasons. Furthermore, a carrier may aid presenting peptides to T-cells. The carrier may be any suitable carrier known to the person skilled in the art, for example a protein or an antigen presenting cell. A carrier protein could be but is not limited to keyhole limpet hemocyanin, serum proteins such as transferrin, bovine serum albumin, human serum albumin, thyroglobulin or ovalbumin, immunoglobulins, or hormones, such as insulin or palmitic acid. For immunization of humans, the carrier may be a physiologically acceptable carrier acceptable to humans and safe. However, tetanus toxoid and/or diptheria toxoid are suitable carriers in one embodiment of the invention. Alternatively, the carrier may be dextrans for example sepharose.

Cytotoxic T-cells (CTLs) recognize an antigen in the form of a peptide bound to an MHC molecule rather than the intact foreign antigen itself. The MHC molecule itself is located at the cell surface of an antigen presenting cell. Thus, an activation of CTLs is only possible if a trimeric complex of peptide antigen, MHC molecule, and APC is present. Correspondingly, it may enhance the immune response if not only the peptide is used for activation of CTLs, but if additionally APCs with the respective MHC molecule are added. Therefore, in some embodiments the vaccine or immunogenic composition according to the present invention additionally contains at least one antigen presenting cell.

The antigen-presenting cell (or stimulator cell) typically has an MHC class I or II molecule on its surface, and in one embodiment is substantially incapable of itself loading the MHC class I or II molecule with the selected antigen. As is described in more detail herein, the MHC class I or II molecule may readily be loaded with the selected antigen in vitro.

CD8+ cell activity may be augmented through the use of CD4+ cells. The identification of CD4 T+ cell epitopes for tumor antigens has attracted interest because many immune based therapies against cancer may be more effective if both CD8+ and CD4+T lymphocytes are used to target a patient's tumor. CD4+ cells are capable of enhancing CD8 T cell responses. Many studies in animal models have clearly demonstrated better results when both CD4+ and CD8+ T cells participate in anti-tumor responses (see e.g., Nishimura et al. (1999) Distinct role of antigen-specific T helper type 1 (TH1) and Th2 cells in tumor eradication in vivo. J Ex Med 190:617-27). Universal CD4+ T cell epitopes have been identified that are applicable to developing therapies against different types of cancer (see e.g., Kobayashi et al. (2008) Current Opinion in Immunology 20:221-27). For example, an HLA-DR restricted helper peptide from tetanus toxoid was used in melanoma vaccines to activate CD4+ T cells non-specifically (see e.g., Slingluff et al. (2007) Immunologic and Clinical Outcomes of a Randomized Phase II Trial of Two Multipeptide Vaccines for Melanoma in the Adjuvant Setting, Clinical Cancer Research 13(21):6386-95). It is contemplated within the scope of the invention that such CD4+ cells may be applicable at three levels that vary in their tumor specificity: 1) a broad level in which universal CD4+ epitopes (e.g., tetanus toxoid) may be used to augment CD8+ cells; 2) an intermediate level in which native, tumor-associated CD4+ epitopes may be used to augment CD8+ cells; and 3) a patient specific level in which neoantigen CD4+ epitopes may be used to augment CD8+ cells in a patient specific manner. Although current algorithms for predicting CD4 epitopes are limited in accuracy, it is a reasonable expectation that many long peptides containing predicted CD8 neoepitopes will also include CD4 epitopes. CD4 epitopes are longer than CD8 epitopes and typically are 10-12 amino acids in length although some can be longer (Kreiter et al, Mutant MHC Class II epitopes drive therapeutic immune responses to cancer, Nature (2015). Thus the neoantigenic epitopes described herein, either in the form of long peptides (>25 amino acids) or nucleic acids encoding such long peptides, may also boost CD4 responses in a tumor and patient-specific manner (level (3) above).

CD8+ cell immunity may also be generated with neoantigen loaded dendritic cell (DC) vaccine. DCs are potent antigen-presenting cells that initiate T cell immunity and can be used as cancer vaccines when loaded with one or more peptides of interest, for example, by direct peptide injection. For example, patients that were newly diagnosed with metastatic melanoma were shown to be immunized against 3 HLA-A*0201-restricted gp100 melanoma antigen-derived peptides with autologous peptide pulsed CD40L/IFN-g-activated mature DCs via an IL-12p70-producing patient DC vaccine (see e.g., Carreno et al (2013) L-12p70-producing patient DC vaccine elicits Tc1-polarized immunity, Journal of Clinical Investigation, 123(8):3383-94 and Ali et al. (2009) In situ regulation of DC subsets and T cells mediates tumor regression in mice, Cancer Immunotherapy, 1(8):1-10). It is contemplated within the scope of the invention that neoantigen loaded DCs may be prepared using the synthetic TLR 3 agonist Polyinosinic-Polycytidylic Acid-poly-L-lysine Carboxymethylcellulose (Poly-ICLC) to stimulate the DCs. Poly-ICLC is a potent individual maturation stimulus for human DCs as assessed by an upregulation of CD83 and CD86, induction of interleukin-12 (IL-12), tumor necrosis factor (TNF), interferon gamma-induced protein 10 (IP-10), interleukin 1 (IL-1), and type I interferons (IFN), and minimal interleukin 10 (IL-10) production. DCs may be differentiated from frozen peripheral blood mononuclear cells (PBMCs) obtained by leukapheresis, while PBMCs may be isolated by Ficoll gradient centrifugation and frozen in aliquots.

Illustratively, the following 7 day activation protocol may be used. Day 1—PBMCs are thawed and plated onto tissue culture flasks to select for monocytes which adhere to the plastic surface after 1-2 hr incubation at 37° C. in the tissue culture incubator. After incubation, the lymphocytes are washed off and the adherent monocytes are cultured for 5 days in the presence of interleukin-4 (IL-4) and granulocyte macrophage-colony stimulating factor (GM-CSF) to differentiate to immature DCs. On Day 6, immature DCs are pulsed with the keyhole limpet hemocyanin (KLH) protein which serves as a control for the quality of the vaccine and may boost the immunogenicity of the vaccine. The DCs are stimulated to mature, loaded with peptide antigens, and incubated overnight. On Day 7, the cells are washed, and frozen in 1 ml aliquots containing 4-20×10(6) cells using a controlled-rate freezer. Lot release testing for the batches of DCs may be performed to meet minimum specifications before the DCs are injected into patients (see e.g., Sabado et al. (2013) Preparation of tumor antigen-loaded mature dendritic cells for immunotherapy, J. Vis Exp. August 1; (78). doi: 10.3791/50085).

A DC vaccine may be incorporated into a scaffold system to facilitate delivery to a patient. Therapeutic treatment of a patients neoplasia with a DC vaccine may utilize a biomaterial system that releases factors that recruit host dendritic cells into the device, differentiates the resident, immature DCs by locally presenting adjuvants (e.g., danger signals) while releasing antigen, and promotes the release of activated, antigen loaded DCs to the lymph nodes (or desired site of action) where the DCs may interact with T cells to generate a potent cytotoxic T lymphocyte response to the cancer neoantigens. Implantable biomaterials may be used to generate a potent cytotoxic T lymphocyte response against a neoplasia in a patient specific manner. The biomaterial-resident dendritic cells may then be activated by exposing them to danger signals mimicking infection, in concert with release of antigen from the biomaterial. The activated dendritic cells then migrate from the biomaterials to lymph nodes to induce a cytotoxic T effector response. This approach has previously been demonstrated to lead to regression of established melanoma in preclinical studies using a lysate prepared from tumor biopsies (see e.g., Ali et al. (2209) In situ regulation of DC subsets and T cells mediates tumor regression in mice, Cancer Immunotherapy 1(8):1-10; Ali et al. (2009) Infection-mimicking materials to program dendritic cells in situ. Nat Mater 8:151-8), and such a vaccine is currently being tested in a Phase I clinical trial recently initiated at the Dana-Farber Cancer Institute. This approach has also been shown to lead to regression of glioblastoma, as well as the induction of a potent memory response to prevent relapse, using the C6 rat glioma model.24 in the current proposal. The ability of such an implantable, biomatrix vaccine delivery scaffold to amplify and sustain tumor specific dendritic cell activation may lead to more robust anti-tumor immunosensitization than can be achieved by traditional subcutaneous or intra-nodal vaccine administrations.

The present invention may include any method for loading a neoantigenic peptide onto a dendritic cell. One such method applicable to the present invention is a microfluidic intracellular delivery system. Such systems cause temporary membrane disruption by rapid mechanical deformation of human and mouse immune cells, thus allowing the intracellular delivery of biomolecules (Sharei et al., 2015, PLOS ONE).

Preferably, the antigen presenting cells are dendritic cells. Suitably, the dendritic cells are autologous dendritic cells that are pulsed with the neoantigenic peptide. The peptide may be any suitable peptide that gives rise to an appropriate T-cell response. T-cell therapy using autologous dendritic cells pulsed with peptides from a tumor associated antigen is disclosed in Murphy et al. (1996) The Prostate 29, 371-380 and Tjua et al. (1997) The Prostate 32, 272-278. In certain embodiments the dendritic cells are targeted using CD141, DEC205, or XCR1 markers. CD141+XCR1+DC's were identified as a subset that may be better suited to the induction of anti-tumor responses (Bachem et al., J. Exp. Med. 207, 1273-1281 (2010); Crozat et al., J. Exp. Med. 207, 1283-1292 (2010); and Gallois & Bhardwaj, Nature Med. 16, 854-856 (2010)).

Thus, in one embodiment of the present invention the vaccine or immunogenic composition containing at least one antigen presenting cell is pulsed or loaded with one or more peptides of the present invention. Alternatively, peripheral blood mononuclear cells (PBMCs) isolated from a patient may be loaded with peptides ex vivo and injected back into the patient. As an alternative the antigen presenting cell comprises an expression construct encoding a peptide of the present invention. The polynucleotide may be any suitable polynucleotide and it is preferred that it is capable of transducing the dendritic cell, thus resulting in the presentation of a peptide and induction of immunity.

The inventive pharmaceutical composition may be compiled so that the selection, number and/or amount of peptides present in the composition covers a high proportion of subjects in the population. The selection may be dependent on the specific type of cancer, the status of the disease, earlier treatment regimens, and, of course, the HLA-haplotypes present in the patient population.

Pharmaceutical compositions comprising the peptide of the invention may be administered to an individual already suffering from cancer. In therapeutic applications, compositions are administered to a patient in an amount sufficient to elicit an effective CTL response to the tumor antigen and to cure or at least partially arrest symptoms and/or complications. An amount adequate to accomplish this is defined as “therapeutically effective dose.” Amounts effective for this use can depend on, e.g., the peptide composition, the manner of administration, the stage and severity of the disease being treated, the weight and general state of health of the patient, and the judgment of the prescribing physician, but generally range for the initial immunization (that is for therapeutic or prophylactic administration) from about 1.0 μg to about 50,000 μg of peptide for a 70 kg patient, followed by boosting dosages or from about 1.0 μg to about 10,000 μg of peptide pursuant to a boosting regimen over weeks to months depending upon the patient's response and condition and possibly by measuring specific CTL activity in the patient's blood. It should be kept in mind that the peptide and compositions of the present invention may generally be employed in serious disease states, that is, life-threatening or potentially life threatening situations, especially when the cancer has metastasized. For therapeutic use, administration should begin as soon as possible after the detection or surgical removal of tumors. This is followed by boosting doses until at least symptoms are substantially abated and for a period thereafter.

The pharmaceutical compositions (e.g., vaccine compositions) for therapeutic treatment are intended for parenteral, topical, nasal, oral or local administration. Preferably, the pharmaceutical compositions are administered parenterally, e.g., intravenously, subcutaneously, intradermally, or intramuscularly. The compositions may be administered at the site of surgical excision to induce a local immune response to the tumor. The invention provides compositions for parenteral administration which comprise a solution of the peptides and vaccine or immunogenic compositions are dissolved or suspended in an acceptable carrier, preferably an aqueous carrier. A variety of aqueous carriers may be used, e.g., water, buffered water, 0.9% saline, 0.3% glycine, hyaluronic acid and the like. These compositions may be sterilized by conventional, well known sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile solution prior to administration. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, etc.

A liposome suspension containing a peptide may be administered intravenously, locally, topically, etc. in a dose which varies according to, inter alia, the manner of administration, the peptide being delivered, and the stage of the disease being treated. For targeting to the immune cells, a ligand, such as, e.g., antibodies or fragments thereof specific for cell surface determinants of the desired immune system cells, can be incorporated into the liposome.

For solid compositions, conventional or nanoparticle nontoxic solid carriers may be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. For oral administration, a pharmaceutically acceptable nontoxic composition is formed by incorporating any of the normally employed excipients, such as those carriers previously listed, and generally 10-95% of active ingredient, that is, one or more peptides of the invention, and more preferably at a concentration of 25%-75%.

For aerosol administration, the immunogenic peptides are preferably supplied in finely divided form along with a surfactant and propellant. Typical percentages of peptides are 0.01%-20% by weight, preferably 1%-10%. The surfactant can, of course, be nontoxic, and preferably soluble in the propellant. Representative of such agents are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride. Mixed esters, such as mixed or natural glycerides may be employed. The surfactant may constitute 0.1%-20%, by weight of the composition, preferably 0.25-5%. The balance of the composition is ordinarily propellant. A carrier can also be included as desired, as with, e.g., lecithin for intranasal delivery.

The peptides and polypeptides of the invention can be readily synthesized chemically utilizing reagents that are free of contaminating bacterial or animal substances (Merrifield RB: Solid phase peptide synthesis. I. The synthesis of a tetrapeptide. J. Am. Chem. Soc. 85:2149-54, 1963).

The peptides and polypeptides of the invention can also be expressed by a vector, e.g., a nucleic acid molecule as herein-discussed, e.g., RNA or a DNA plasmid, a viral vector such as a poxvirus, e.g., orthopox virus, avipox virus, or adenovirus, AAV or lentivirus. This approach involves the use of a vector to express nucleotide sequences that encode the peptide of the invention. Upon introduction into an acutely or chronically infected host or into a noninfected host, the vector expresses the immunogenic peptide, and thereby elicits a host CTL response.

For therapeutic or immunization purposes, nucleic acids encoding the peptide of the invention and optionally one or more of the peptides described herein can also be administered to the patient. A number of methods are conveniently used to deliver the nucleic acids to the patient. For instance, the nucleic acid can be delivered directly, as “naked DNA”. This approach is described, for instance, in Wolff et al., Science 247: 1465-1468 (1990) as well as U.S. Pat. Nos. 5,580,859 and 5,589,466. The nucleic acids can also be administered using ballistic delivery as described, for instance, in U.S. Pat. No. 5,204,253. Particles comprised solely of DNA can be administered. Alternatively, DNA can be adhered to particles, such as gold particles. Generally, a plasmid for a vaccine or immunological composition can comprise DNA encoding an antigen (e.g., one or more neoantigens) operatively linked to regulatory sequences which control expression or expression and secretion of the antigen from a host cell, e.g., a mammalian cell; for instance, from upstream to downstream, DNA for a promoter, such as a mammalian virus promoter (e.g., a CMV promoter such as an hCMV or mCMV promoter, e.g., an early-intermediate promoter, or an SV40 promoter—see documents cited or incorporated herein for useful promoters), DNA for a eukaryotic leader peptide for secretion (e.g., tissue plasminogen activator), DNA for the neoantigen(s), and DNA encoding a terminator (e.g., the 3′ UTR transcriptional terminator from the gene encoding Bovine Growth Hormone or bGH polyA). A composition can contain more than one plasmid or vector, whereby each vector contains and expresses a different neoantigen. Mention is also made of Wasmoen U.S. Pat. No. 5,849,303, and Dale U.S. Pat. No. 5,811,104, whose text may be useful. DNA or DNA plasmid formulations can be formulated with or inside cationic lipids; and, as to cationic lipids, as well as adjuvants, mention is also made of Loosmore U.S. Patent Application 2003/0104008. Also, teachings in Audonnet U.S. Pat. Nos. 6,228,846 and 6,159,477 may be relied upon for DNA plasmid teachings that can be employed in constructing and using DNA plasmids that contain and express in vivo.

The nucleic acids can also be delivered complexed to cationic compounds, such as cationic lipids. Lipid-mediated gene delivery methods are described, for instance, in WO1996/18372; WO 1993/24640; Mannino & Gould-Fogerite, BioTechniques 6(7): 682-691 (1988); U.S. Pat. No. 5,279,833; WO 1991/06309; and Feigner et al., Proc. Natl. Acad. Sci. USA 84: 7413-7414 (1987).

RNA encoding the peptide of interest (e.g., mRNA) can also be used for delivery (see, e.g., Kiken et al, 2011; Su et al, 2011; see also U.S. Pat. No. 8,278,036; Halabi et al. J Clin Oncol (2003) 21:1232-1237; Petsch et al, Nature Biotechnology 2012 Dec. 7; 30(12):1210-6).

Viral vectors as described herein can also be used to deliver the neoantigenic peptides of the invention. Vectors can be administered so as to have in vivo expression and response akin to doses and/or responses elicited by antigen administration.

A preferred means of administering nucleic acids encoding the peptide of the invention uses minigene constructs encoding multiple epitopes. To create a DNA sequence encoding the selected CTL epitopes (minigene) for expression in human cells, the amino acid sequences of the epitopes are reverse translated. A human codon usage table is used to guide the codon choice for each amino acid. These epitope-encoding DNA sequences are directly adjoined, creating a continuous polypeptide sequence. To optimize expression and/or immunogenicity, additional elements can be incorporated into the minigene design. Examples of amino acid sequence that could be reverse translated and included in the minigene sequence include: helper T lymphocyte, epitopes, a leader (signal) sequence, and an endoplasmic reticulum retention signal. In addition, MHC presentation of CTL epitopes may be improved by including synthetic (e.g. poly-alanine) or naturally-occurring flanking sequences adjacent to the CTL epitopes.

The minigene sequence is converted to DNA by assembling oligonucleotides that encode the plus and minus strands of the minigene. Overlapping oligonucleotides (30-100 bases long) are synthesized, phosphorylated, purified and annealed under appropriate conditions using well known techniques. The ends of the oligonucleotides are joined using T4 DNA ligase. This synthetic minigene, encoding the CTL epitope polypeptide, can then cloned into a desired expression vector.

Standard regulatory sequences well known to those of skill in the art are included in the vector to ensure expression in the target cells. Several vector elements are required: a promoter with a down-stream cloning site for minigene insertion; a polyadenylation signal for efficient transcription termination; an E. coli origin of replication; and an E. coli selectable marker (e.g. ampicillin or kanamycin resistance). Numerous promoters can be used for this purpose, e.g., the human cytomegalovirus (hCMV) promoter. See, U.S. Pat. Nos. 5,580,859 and 5,589,466 for other suitable promoter sequences.

Additional vector modifications may be desired to optimize minigene expression and immunogenicity. In some cases, introns are required for efficient gene expression, and one or more synthetic or naturally-occurring introns could be incorporated into the transcribed region of the minigene. The inclusion of mRNA stabilization sequences can also be considered for increasing minigene expression. It has recently been proposed that immuno stimulatory sequences (ISSs or CpGs) play a role in the immunogenicity of DNA′ vaccines. These sequences could be included in the vector, outside the minigene coding sequence, if found to enhance immunogenicity.

In some embodiments, a bicistronic expression vector, to allow production of the minigene-encoded epitopes and a second protein included to enhance or decrease immunogenicity can be used. Examples of proteins or polypeptides that could beneficially enhance the immune response if co-expressed include cytokines (e.g., IL2, IL12, GM-CSF), cytokine-inducing molecules (e.g. LeIF) or costimulatory molecules. Helper (HTL) epitopes could be joined to intracellular targeting signals and expressed separately from the CTL epitopes. This would allow direction of the HTL epitopes to a cell compartment different than the CTL epitopes. If required, this could facilitate more efficient entry of HTL epitopes into the MHC class II pathway, thereby improving CTL induction. In contrast to CTL induction, specifically decreasing the immune response by co-expression of immunosuppressive molecules (e.g. TGF-β) may be beneficial in certain diseases.

Once an expression vector is selected, the minigene is cloned into the polylinker region downstream of the promoter. This plasmid is transformed into an appropriate E. coli strain, and DNA is prepared using standard techniques. The orientation and DNA sequence of the minigene, as well as all other elements included in the vector, are confirmed using restriction mapping and DNA sequence analysis. Bacterial cells harboring the correct plasmid can be stored as a master cell bank and a working cell bank.

Purified plasmid DNA can be prepared for injection using a variety of formulations. The simplest of these is reconstitution of lyophilized DNA in sterile phosphate-buffer saline (PBS). A variety of methods have been described, and new techniques may become available. As noted herein, nucleic acids are conveniently formulated with cationic lipids. In addition, glycolipids, fusogenic liposomes, peptides and compounds referred to collectively as protective, interactive, non-condensing (PINC) could also be complexed to purified plasmid DNA to influence variables such as stability, intramuscular dispersion, or trafficking to specific organs or cell types.

Target cell sensitization can be used as a functional assay for expression and MHC class I presentation of minigene-encoded CTL epitopes. The plasmid DNA is introduced into a mammalian cell line that is suitable as a target for standard CTL chromium release assays. The transfection method used is dependent on the final formulation. Electroporation can be used for “naked” DNA, whereas cationic lipids allow direct in vitro transfection. A plasmid expressing green fluorescent protein (GFP) can be co-transfected to allow enrichment of transfected cells using fluorescence activated cell sorting (FACS). These cells are then chromium-51 labeled and used as target cells for epitope-specific CTL lines. Cytolysis, detected by 51 Cr release, indicates production of MHC presentation of mini gene-encoded CTL epitopes.

In vivo immunogenicity is a second approach for functional testing of minigene DNA formulations. Transgenic mice expressing appropriate human MHC molecules are immunized with the DNA product. The dose and route of administration are formulation dependent (e.g. IM for DNA in PBS, IP for lipid-complexed DNA). Twenty-one days after immunization, splenocytes are harvested and restimulated for 1 week in the presence of peptides encoding each epitope being tested. These effector cells (CTLs) are assayed for cytolysis of peptide-loaded, chromium-51 labeled target cells using standard techniques. Lysis of target cells sensitized by MHC loading of peptides corresponding to minigene-encoded epitopes demonstrates DNA vaccine function for in vivo induction of CTLs.

Peptides may be used to elicit CTL ex vivo, as well. The resulting CTL, can be used to treat chronic tumors in patients in need thereof that do not respond to other conventional forms of therapy, or does not respond to a peptide vaccine approach of therapy. Ex vivo CTL responses to a particular tumor antigen are induced by incubating in tissue culture the patient's CTL precursor cells (CTLp) together with a source of antigen-presenting cells (APC) and the appropriate peptide. After an appropriate incubation time (typically 1-4 weeks), in which the CTLp are activated and mature and expand into effector CTL, the cells are infused back into the patient, where they destroy their specific target cell (i.e., a tumor cell). In order to optimize the in vitro conditions for the generation of specific cytotoxic T cells, the culture of stimulator cells are maintained in an appropriate serum-free medium.

Prior to incubation of the stimulator cells with the cells to be activated, e.g., precursor CD8+ cells, an amount of antigenic peptide is added to the stimulator cell culture, of sufficient quantity to become loaded onto the human Class I molecules to be expressed on the surface of the stimulator cells. In the present invention, a sufficient amount of peptide is an amount that allows about 200, and preferably 200 or more, human Class I MHC molecules loaded with peptide to be expressed on the surface of each stimulator cell. Preferably, the stimulator cells are incubated with >2 μg/ml peptide. For example, the stimulator cells are incubates with >3, 4, 5, 10, 15, or more μg/ml peptide.

Resting or precursor CD8+ cells are then incubated in culture with the appropriate stimulator cells for a time period sufficient to activate the CD8+ cells. Preferably, the CD8+ cells are activated in an antigen-specific manner. The ratio of resting or precursor CD8+(effector) cells to stimulator cells may vary from individual to individual and may further depend upon variables such as the amenability of an individual's lymphocytes to culturing conditions and the nature and severity of the disease condition or other condition for which the within-described treatment modality is used. Preferably, however, the lymphocyte: stimulator cell ratio is in the range of about 30:1 to 300:1. The effector/stimulator culture may be maintained for as long a time as is necessary to stimulate a therapeutically useable or effective number of CD8+ cells.

The induction of CTL in vitro requires the specific recognition of peptides that are bound to allele specific MHC class I molecules on APC. The number of specific MHC/peptide complexes per APC is crucial for the stimulation of CTL, particularly in primary immune responses. While small amounts of peptide/MHC complexes per cell are sufficient to render a cell susceptible to lysis by CTL, or to stimulate a secondary CTL response, the successful activation of a CTL precursor (pCTL) during primary response requires a significantly higher number of MHC/peptide complexes. Peptide loading of empty major histocompatability complex molecules on cells allows the induction of primary cytotoxic T lymphocyte responses.

Since mutant cell lines do not exist for every human MHC allele, it is advantageous to use a technique to remove endogenous MHC-associated peptides from the surface of APC, followed by loading the resulting empty MHC molecules with the immunogenic peptides of interest. The use of non-transformed (non-tumorigenic), noninfected cells, and preferably, autologous cells of patients as APC is desirable for the design of CTL induction protocols directed towards development of ex vivo CTL therapies. This application discloses methods for stripping the endogenous MHC-associated peptides from the surface of APC followed by the loading of desired peptides.

A stable MHC class I molecule is a trimeric complex formed of the following elements: 1) a peptide usually of 8-10 residues, 2) a transmembrane heavy polymorphic protein chain which bears the peptide-binding site in its a1 and a2 domains, and 3) a non-covalently associated non-polymorphic light chain, p2microglobuiin. Removing the bound peptides and/or dissociating the p2microglobulin from the complex renders the MHC class I molecules nonfunctional and unstable, resulting in rapid degradation. All MHC class I molecules isolated from PBMCs have endogenous peptides bound to them. Therefore, the first step is to remove all endogenous peptides bound to MHC class I molecules on the APC without causing their degradation before exogenous peptides can be added to them.

Two possible ways to free up MHC class I molecules of bound peptides include lowering the culture temperature from 37° C. to 26° C. overnight to destablize p2microglobulin and stripping the endogenous peptides from the cell using a mild acid treatment. The methods release previously bound peptides into the extracellular environment allowing new exogenous peptides to bind to the empty class I molecules. The cold-temperature incubation method enables exogenous peptides to bind efficiently to the MHC complex, but requires an overnight incubation at 26° C. which may slow the cell's metabolic rate. It is also likely that cells not actively synthesizing MHC molecules (e.g., resting PBMC) would not produce high amounts of empty surface MHC molecules by the cold temperature procedure.

Harsh acid stripping involves extraction of the peptides with trifluoroacetic acid, pH 2, or acid denaturation of the immunoaffinity purified class I-peptide complexes. These methods are not feasible for CTL induction, since it is important to remove the endogenous peptides while preserving APC viability and an optimal metabolic state which is critical for antigen presentation. Mild acid solutions of pH 3 such as glycine or citrate-phosphate buffers have been used to identify endogenous peptides and to identify tumor associated T cell epitopes. The treatment is especially effective, in that only the MHC class I molecules are destabilized (and associated peptides released), while other surface antigens remain intact, including MHC class II molecules. Most importantly, treatment of cells with the mild acid solutions do not affect the cell's viability or metabolic state. The mild acid treatment is rapid since the stripping of the endogenous peptides occurs in two minutes at 4° C. and the APC is ready to perform its function after the appropriate peptides are loaded. The technique is utilized herein to make peptide-specific APCs for the generation of primary antigen-specific CTL. The resulting APC are efficient in inducing peptide-specific CD8+CTL.

Activated CD8+ cells may be effectively separated from the stimulator cells using one of a variety of known methods. For example, monoclonal antibodies specific for the stimulator cells, for the peptides loaded onto the stimulator cells, or for the CD8+ cells (or a segment thereof) may be utilized to bind their appropriate complementary ligand. Antibody-tagged molecules may then be extracted from the stimulator-effector cell admixture via appropriate means, e.g., via well-known immunoprecipitation or immunoassay methods.

Effective, cytotoxic amounts of the activated CD8+ cells can vary between in vitro and in vivo uses, as well as with the amount and type of cells that are the ultimate target of these killer cells. The amount can also vary depending on the condition of the patient and should be determined via consideration of all appropriate factors by the practitioner. Preferably, however, about 1×10⁶ to about 1×10¹², more preferably about 1×10⁸ to about 1×10¹¹, and even more preferably, about 1×10⁹ to about 1×10¹⁰ activated CD8+ cells are utilized for adult humans, compared to about 5×10⁶-5×10⁷ cells used in mice.

Preferably, as discussed herein, the activated CD8+ cells are harvested from the cell culture prior to administration of the CD8+ cells to the individual being treated. It is important to note, however, that unlike other present and proposed treatment modalities, the present method uses a cell culture system that is not tumorigenic. Therefore, if complete separation of stimulator cells and activated CD8+ cells are not achieved, there is no inherent danger known to be associated with the administration of a small number of stimulator cells, whereas administration of mammalian tumor-promoting cells may be extremely hazardous.

Methods of re-introducing cellular components are known in the art and include procedures such as those exemplified in U.S. Pat. No. 4,844,893 to Honsik, et al. and U.S. Pat. No. 4,690,915 to Rosenberg. For example, administration of activated CD8+ cells via intravenous infusion is appropriate.

The practice of the present invention employs, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are well within the purview of the skilled artisan. Such techniques are explained fully in the literature, such as, “Molecular Cloning: A Laboratory Manual”, second edition (Sambrook, 1989); “Oligonucleotide Synthesis” (Gait, 1984); “Animal Cell Culture” (Freshney, 1987); “Methods in Enzymology” “Handbook of Experimental Immunology” (Wei, 1996); “Gene Transfer Vectors for Mammalian Cells” (Miller and Calos, 1987); “Current Protocols in Molecular Biology” (Ausubel, 1987); “PCR: The Polymerase Chain Reaction”, (Mullis, 1994); “Current Protocols in Immunology” (Coligan, 1991). These techniques are applicable to the production of the polynucleotides and polypeptides of the invention, and, as such, may be considered in making and practicing the invention. Particularly useful techniques for particular embodiments are discussed in the sections that follow.

Therapeutic Methods

The present invention provides methods of inducing a neoplasia/tumor specific immune response in a subject, vaccinating against a neoplasia/tumor, treating and or alleviating a symptom of cancer in a subject by administering the subject a plurality of neoantigenic peptides or composition of the invention.

According to the invention, the herein-described neoplasia vaccine or immunogenic composition may be used for a patient that has been diagnosed as having cancer, or at risk of developing cancer.

The claimed combination of the invention is administered in an amount sufficient to induce a CTL response.

Additional Therapies

The tumor specific neoantigen peptides and pharmaceutical compositions described herein can also be administered in a combination therapy with another agent, for example a therapeutic agent. In certain embodiments, the additional agents can be, but are not limited to, chemotherapeutic agents, anti-angiogenesis agents and agents that reduce immune-suppression.

The neoplasia vaccine or immunogenic composition can be administered before, during, or after administration of the additional agent. In embodiments, the neoplasia vaccine or immunogenic composition is administered before the first administration of the additional agent. In other embodiments, the neoplasia vaccine or immunogenic composition is administered after the first administration of the additional therapeutic agent (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days or more). In embodiments, the neoplasia vaccine or immunogenic composition is administered simultaneously with the first administration of the additional therapeutic agent.

The therapeutic agent is for example, a chemotherapeutic or biotherapeutic agent, radiation, or immunotherapy. Any suitable therapeutic treatment for a particular cancer may be administered. Examples of chemotherapeutic and biotherapeutic agents include, but are not limited to, an angiogenesis inhibitor, such ashydroxy angiostatin K1-3, DL-α-Difluoromethyl-ornithine, endostatin, fumagillin, genistein, minocycline, staurosporine, and thalidomide; a DNA intercaltor/cross-linker, such as Bleomycin, Carboplatin, Carmustine, Chlorambucil, Cyclophosphamide, cis-Diammineplatinum(II) dichloride (Cisplatin), Melphalan, Mitoxantrone, and Oxaliplatin; a DNA synthesis inhibitor, such as (±)-Amethopterin (Methotrexate), 3-Amino-1,2,4-benzotriazine 1,4-dioxide, Aminopterin, Cytosine β-D-arabinofuranoside, 5-Fluoro-5′-deoxyuridine, 5-Fluorouracil, Ganciclovir, Hydroxyurea, and Mitomycin C; a DNA-RNA transcription regulator, such as Actinomycin D, Daunorubicin, Doxorubicin, Homoharringtonine, and Idarubicin; an enzyme inhibitor, such as S(+)-Camptothecin, Curcumin, (−)-Deguelin, 5,6-Dichlorobenzimidazole 1-β-D-ribofuranoside, Etoposide, Formestane, Fostriecin, Hispidin, 2-Imino-1-imidazoli-dineacetic acid (Cyclocreatine), Mevinolin, Trichostatin A, Tyrphostin AG 34, and Tyrphostin AG 879; a gene regulator, such as 5-Aza-2′-deoxycytidine, 5-Azacytidine, Cholecalciferol (Vitamin D3), 4-Hydroxytamoxifen, Melatonin, Mifepristone, Raloxifene, all trans-Retinal (Vitamin A aldehyde), Retinoic acid all trans (Vitamin A acid), 9-cis-Retinoic Acid, 13-cis-Retinoic acid, Retinol (Vitamin A), Tamoxifen, and Troglitazone; a microtubule inhibitor, such as Colchicine, docetaxel, Dolastatin 15, Nocodazole, Paclitaxel, Podophyllotoxin, Rhizoxin, Vinblastine, Vincristine, Vindesine, and Vinorelbine (Navelbine); and an unclassified therapeutic agent, such as 17-(Allylamino)-17-demethoxygeldanamycin, 4-Amino-1,8-naphthalimide, Apigenin, Brefeldin A, Cimetidine, Dichloromethylene-diphosphonic acid, Leuprolide (Leuprorelin), Luteinizing Hormone-Releasing Hormone, Pifithrin-α, Rapamycin, Sex hormone-binding globulin, Thapsigargin, and Urinary trypsin inhibitor fragment (Bikunin). The therapeutic agent may be altretamine, amifostine, asparaginase, capecitabine, cladribine, cisapride, cytarabine, dacarbazine (DTIC), dactinomycin, dronabinol, epoetin alpha, filgrastim, fludarabine, gemcitabine, granisetron, ifosfamide, irinotecan, lansoprazole, levamisole, leucovorin, megestrol, mesna, metoclopramide, mitotane, omeprazole, ondansetron, pilocarpine, prochloroperazine, or topotecan hydrochloride. The therapeutic agent may be a monoclonal antibody or small molecule such as rituximab (Rituxan®), alemtuzumab (Campath®), Bevacizumab (Avastin®), Cetuximab (Erbitux®), panitumumab (Vectibix®), and trastuzumab (Herceptin®), Vemurafenib (Zelboraf@) imatinib mesylate (Gleevec®), erlotinib (Tarceva®), gefitinib (Iressa®), Vismodegib (Erivedge™), 90Y-ibritumomab tiuxetan, 131I-tositumomab, ado-trastuzumab emtansine, lapatinib (Tykerb®), pertuzumab (Perjeta™), ado-trastuzumab emtansine (Kadcyla™), regorafenib (Stivarga®), sunitinib (Sutent®), Denosumab (Xgeva®), sorafenib (Nexavar®), pazopanib (Votrient®), axitinib (Inlyta®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), ofatumumab (Arzerra®), obinutuzumab (Gazyva™), ibrutinib (Imbruvica™), idelalisib (Zydelig®), crizotinib (Xalkori®), erlotinib (Tarceva®), afatinib dimaleate (Gilotrif®), ceritinib (LDK378/Zykadia), Tositumomab and 131I-tositumomab (Bexxar®), ibritumomab tiuxetan (Zevalin®), brentuximab vedotin (Adcetris®), bortezomib (Velcade®), siltuximab (Sylvant™), trametinib (Mekinist®), dabrafenib (Tafinlar®), pembrolizumab (Keytruda®), carfilzomib (Kyprolis®), Ramucirumab (Cyramza™), Cabozantinib (Cometriq™), vandetanib (Caprelsa®), Optionally, the therapeutic agent is a neoantigen. The therapeutic agent may be a cytokine such as interferons (INFs), interleukins (ILs), or hematopoietic growth factors. The therapeutic agent may be INF-α, IL-2, Aldesleukin, IL-2, Erythropoietin, Granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor. The therapeutic agent may be a targeted therapy such as toremifene (Fareston®), fulvestrant (Faslodex®), anastrozole (Arimidex®), exemestane (Aromasin®), letrozole (Femara®), ziv-aflibercept (Zaltrap®), Alitretinoin (Panretin®), temsirolimus (Torisel®), Tretinoin (Vesanoid®), denileukin diftitox (Ontak®), vorinostat (Zolinza®), romidepsin (Istodax®), bexarotene (Targretin®), pralatrexate (Folotyn®), lenaliomide (Revlimid®), belinostat (Beleodaq™), lenaliomide (Revlimid®), pomalidomide (Pomalyst®), Cabazitaxel (Jevtana®), enzalutamide (Xtandi®), abiraterone acetate (Zytiga®), radium 223 chloride (Xofigo®), or everolimus (Afinitor®). Additionally, the therapeutic agent may be an epigenetic targeted drug such as HDAC inhibitors, kinase inhibitors, DNA methyltransferase inhibitors, histone demethylase inhibitors, or histone methylation inhibitors. The epigenetic drugs may be Azacitidine (Vidaza), Decitabine (Dacogen), Vorinostat (Zolinza), Romidepsin (Istodax), or Ruxolitinib (Jakafi). For prostate cancer treatment, a preferred chemotherapeutic agent with which anti-CTLA-4 can be combined is paclitaxel (TAXOL).

In certain embodiments, the one or more additional agents are one or more anti-glucocorticoid-induced tumor necrosis factor family receptor (GITR) agonistic antibodies. GITR is a costimulatory molecule for T lymphocytes, modulates innate and adaptive immune system and has been found to participate in a variety of immune responses and inflammatory processes. GITR was originally described by Nocentini et al. after being cloned from dexamethasone-treated murine T cell hybridomas (Nocentini et al. Proc Natl Acad Sci USA 94:6216-6221.1997). Unlike CD28 and CTLA-4, GITR has a very low basal expression on naive CD4+ and CD8+ T cells (Ronchetti et al. Eur J Immunol 34:613-622. 2004). The observation that GITR stimulation has immunostimulatory effects in vitro and induced autoimmunity in vivo prompted the investigation of the antitumor potency of triggering this pathway. A review of Modulation Of Ctla 4 And Gitr For Cancer Immunotherapy can be found in Cancer Immunology and Immunotherapy (Avogadri et al. Current Topics in Microbiology and Immunology 344. 2011). Other agents that can contribute to relief of immune suppression include checkpoint inhibitors targeted at another member of the CD28/CTLA4 Ig superfamily such as BTLA, LAG3, ICOS, PDL1 or KIR (Page et a, Annual Review of Medicine 65:27 (2014)). In further additional embodiments, the checkpoint inhibitor is targeted at a member of the TNFR superfamily such as CD40, OX40, CD137, GITR, CD27 or TIM-3. In some cases targeting a checkpoint inhibitor is accomplished with an inhibitory antibody or similar molecule. In other cases, it is accomplished with an agonist for the target; examples of this class include the stimulatory targets OX40 and GITR.

In certain embodiments, the one or more additional agents are synergistic in that they increase immunogenicity after treatment. In one embodiment the additional agent allows for lower toxicity and/or lower discomfort due to lower doses of the additional therapeutic agents or any components of the combination therapy described herein. In another embodiment the additional agent results in longer lifespan due to increased effectiveness of the combination therapy described herein. Chemotherapeutic treatments that enhance the immunological response in a patient have been reviewed (Zitvogel et al., Immunological aspects of cancer chemotherapy. Nat Rev Immunol. 2008 January; 8(1):59-73). Additionally, chemotherapeutic agents can be administered safely with immunotherapy without inhibiting vaccine specific T-cell responses (Perez et al., A new era in anticancer peptide vaccines. Cancer May 2010). In one embodiment the additional agent is administered to increase the efficacy of the therapy described herein. In one embodiment the additional agent is a chemotherapy treatment. In one embodiment low doses of chemotherapy potentiate delayed-type hypersensitivity (DTH) responses. In one embodiment the chemotherapy agent targets regulatory T-cells. In one embodiment cyclophosphamide is the therapeutic agent. In one embodiment cyclophosphamide is administered prior to vaccination. In one embodiment cyclophosphamide is administered as a single dose before vaccination (Walter et al., Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nature Medicine; 18:8 2012). In another embodiment, cyclophosphamide is administered according to a metronomic program, where a daily dose is administered for one month (Ghiringhelli et al., Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 2007 56:641-648). In another embodiment taxanes are administered before vaccination to enhance T-cell and NK-cell functions (Zitvogel et al., 2008). In another embodiment a low dose of a chemotherapeutic agent is administered with the therapy described herein. In one embodiment the chemotherapeutic agent is estramustine. In one embodiment the cancer is hormone resistant prostate cancer. A ≥50% decrease in serum prostate specific antigen (PSA) was seen in 8.7% of advanced hormone refractory prostate cancer patients by personalized vaccination alone, whereas such a decrease was seen in 54% of patients when the personalized vaccination was combined with a low dose of estramustine (Itoh et al., Personalized peptide vaccines: A new therapeutic modality for cancer. Cancer Sci 2006; 97: 970-976). In another embodiment glucocorticoids are administered with or before the therapy described herein (Zitvogel et al., 2008). In another embodiment glucocorticoids are administered after the therapy described herein. In another embodiment Gemcitabine is administered before, simultaneously, or after the therapy described herein to enhance the frequency of tumor specific CTL precursors (Zitvogel et al., 2008). In another embodiment 5-fluorouracil is administered with the therapy described herein as synergistic effects were seen with a peptide based vaccine (Zitvogel et al., 2008). In another embodiment an inhibitor of Braf, such as Vemurafenib, is used as an additional agent. Braf inhibition has been shown to be associated with an increase in melanoma antigen expression and T-cell infiltrate and a decrease in immunosuppressive cytokines in tumors of treated patients (Frederick et al., BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013; 19:1225-1231). In another embodiment an inhibitor of tyrosine kinases is used as an additional agent. In one embodiment the tyrosine kinase inhibitor is used before vaccination with the therapy described herein. In one embodiment the tyrosine kinase inhibitor is used simultaneously with the therapy described herein. In another embodiment the tyrosine kinase inhibitor is used to create a more immune permissive environment. In another embodiment the tyrosine kinase inhibitor is sunitinib or imatinib mesylate. It has previously been shown that favorable outcomes could be achieved with sequential administration of continuous daily dosing of sunitinib and recombinant vaccine (Farsaci et al., Consequence of dose scheduling of sunitinib on host immune response elements and vaccine combination therapy. Int J Cancer; 130: 1948-1959). Sunitinib has also been shown to reverse type-1 immune suppression using a daily dose of 50 mg/day (Finke et al., Sunitinib Reverses Type-1 Immune Suppression and Decreases T-Regulatory Cells in Renal Cell Carcinoma Patients. Clin Cancer Res 2008; 14(20)). In another embodiment targeted therapies are administered in combination with the therapy described herein. Doses of targeted therapies has been described previously (Alvarez, Present and future evolution of advanced breast cancer therapy. Breast Cancer Research 2010, 12(Suppl 2):S1). In another embodiment temozolomide is administered with the therapy described herein. In one embodiment temozolomide is administered at 200 mg/day for 5 days every fourth week of a combination therapy with the therapy described herein. Results of a similar strategy have been shown to have low toxicity (Kyte et al., Telomerase Peptide Vaccination Combined with Temozolomide: A Clinical Trial in Stage IV Melanoma Patients. Clin Cancer Res; 17(13) 2011). In another embodiment the therapy is administered with an additional therapeutic agent that results in lymphopenia. In one embodiment the additional agent is temozolomide. An immune response can still be induced under these conditions (Sampson et al., Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro-Oncology 13(3):324-333, 2011).

Patients in need thereof may receive a series of priming vaccinations with a mixture of tumor-specific peptides. Additionally, over a 4 week period the priming may be followed by two boosts during a maintenance phase. All vaccinations are subcutaneously delivered. The vaccine or immunogenic composition is evaluated for safety, tolerability, immune response and clinical effect in patients and for feasibility of producing vaccine or immunogenic composition and successfully initiating vaccination within an appropriate time frame. The first cohort can consist of 5 patients, and after safety is adequately demonstrated, an additional cohort of 10 patients may be enrolled. Peripheral blood is extensively monitored for peptide-specific T-cell responses and patients are followed for up to two years to assess disease recurrence.

Administering a Combination Therapy Consistent with Standard of Care

In another aspect, the therapy described herein provides selecting the appropriate point to administer a combination therapy in relation to and within the standard of care for the cancer being treated for a patient in need thereof. The studies described herein show that the combination therapy can be effectively administered even within the standard of care that includes surgery, radiation, or chemotherapy. The standards of care for the most common cancers can be found on the website of National Cancer Institute (www.cancer.gov/cancertopics). The standard of care is the current treatment that is accepted by medical experts as a proper treatment for a certain type of disease and that is widely used by healthcare professionals. Standard or care is also called best practice, standard medical care, and standard therapy. Standards of Care for cancer generally include surgery, lymph node removal, radiation, chemotherapy, targeted therapies, antibodies targeting the tumor, and immunotherapy. Immunotherapy can include checkpoint blockers (CBP), chimeric antigen receptors (CARs), and adoptive T-cell therapy. The combination therapy described herein can be incorporated within the standard of care. The combination therapy described herein may also be administered where the standard of care has changed due to advances in medicine.

Incorporation of the combination therapy described herein may depend on a treatment step in the standard of care that can lead to activation of the immune system. Treatment steps that can activate and function synergistically with the combination therapy have been described herein. The therapy can be advantageously administered simultaneously or after a treatment that activates the immune system.

Incorporation of the combination therapy described herein may depend on a treatment step in the standard of care that causes the immune system to be suppressed. Such treatment steps may include irradiation, high doses of alkylating agents and/or methotrexate, steroids such as glucosteroids, surgery, such as to remove the lymph nodes, imatinib mesylate, high doses of TNF, and taxanes (Zitvogel et al., 2008). The combination therapy may be administered before such steps or may be administered after.

In one embodiment the combination therapy may be administered after bone marrow transplants and peripheral blood stem cell transplantation. Bone marrow transplantation and peripheral blood stem cell transplantation are procedures that restore stem cells that were destroyed by high doses of chemotherapy and/or radiation therapy. After being treated with high-dose anticancer drugs and/or radiation, the patient receives harvested stem cells, which travel to the bone marrow and begin to produce new blood cells. A “mini-transplant” uses lower, less toxic doses of chemotherapy and/or radiation to prepare the patient for transplant. A “tandem transplant” involves two sequential courses of high-dose chemotherapy and stem cell transplant. In autologous transplants, patients receive their own stem cells. In syngeneic transplants, patients receive stem cells from their identical twin. In allogeneic transplants, patients receive stem cells from their brother, sister, or parent. A person who is not related to the patient (an unrelated donor) also may be used. In some types of leukemia, the graft-versus-tumor (GVT) effect that occurs after allogeneic BMT and PBSCT is crucial to the effectiveness of the treatment. GVT occurs when white blood cells from the donor (the graft) identify the cancer cells that remain in the patient's body after the chemotherapy and/or radiation therapy (the tumor) as foreign and attack them. Immunotherapy with the combination therapy described herein can take advantage of this by vaccinating after a transplant. Additionally, the transferred cells may be presented with neoantigens of the combination therapy described herein before transplantation.

In one embodiment the combination therapy is administered to a patient in need thereof with a cancer that requires surgery. In one embodiment the combination therapy described herein is administered to a patient in need thereof in a cancer where the standard of care is primarily surgery followed by treatment to remove possible micro-metastases, such as breast cancer. Breast cancer is commonly treated by various combinations of surgery, radiation therapy, chemotherapy, and hormone therapy based on the stage and grade of the cancer. Adjuvant therapy for breast cancer is any treatment given after primary therapy to increase the chance of long-term survival. Neoadjuvant therapy is treatment given before primary therapy. Adjuvant therapy for breast cancer is any treatment given after primary therapy to increase the chance of long-term disease-free survival. Primary therapy is the main treatment used to reduce or eliminate the cancer. Primary therapy for breast cancer usually includes surgery, a mastectomy (removal of the breast) or a lumpectomy (surgery to remove the tumor and a small amount of normal tissue around it; a type of breast-conserving surgery). During either type of surgery, one or more nearby lymph nodes are also removed to see if cancer cells have spread to the lymphatic system. When a woman has breast-conserving surgery, primary therapy almost always includes radiation therapy. Even in early-stage breast cancer, cells may break away from the primary tumor and spread to other parts of the body (metastasize). Therefore, doctors give adjuvant therapy to kill any cancer cells that may have spread, even if they cannot be detected by imaging or laboratory tests.

In one embodiment the combination therapy is administered consistent with the standard of care for Ductal carcinoma in situ (DCIS). The standard of care for this breast cancer type is:

1. Breast-conserving surgery and radiation therapy with or without tamoxifen.

2. Total mastectomy with or without tamoxifen.

3. Breast-conserving surgery without radiation therapy.

The combination therapy may be administered before breast conserving surgery or total mastectomy to shrink the tumor before surgery. In another embodiment the combination therapy can be administered as an adjuvant therapy to remove any remaining cancer cells. In another embodiment patients diagnosed with stage I, II, IIIA, and Operable IIIC breast cancer are treated with the combination therapy as described herein. The standard of care for this breast cancer type is:

1. Local-regional treatment:

-   -   Breast-conserving therapy (lumpectomy, breast radiation, and         surgical staging of the axilla).     -   Modified radical mastectomy (removal of the entire breast with         level I-II axillary dissection) with or without breast         reconstruction.     -   Sentinel node biopsy.

2. Adjuvant radiation therapy postmastectomy in axillary node-positive tumors:

-   -   For one to three nodes: unclear role for regional radiation         (infra/supraclavicular nodes, internal mammary nodes, axillary         nodes, and chest wall).     -   For more than four nodes or extranodal involvement: regional         radiation is advised.

3. Adjuvant systemic therapy

In one embodiment the combination therapy is administered as a neoadjuvant therapy to shrink the tumor. In another embodiment the combination is administered as an adjuvant systemic therapy.

In another embodiment patients diagnosed with inoperable stage IIIB or IIIC or inflammatory breast cancer are treated with the combination therapy as described herein. The standard of care for this breast cancer type is:

1. Multimodality therapy delivered with curative intent is the standard of care for patients with clinical stage IIIB disease.

2. Initial surgery is generally limited to biopsy to permit the determination of histology, estrogen-receptor (ER) and progesterone-receptor (PR) levels, and human epidermal growth factor receptor 2 (HER2/neu) overexpression. Initial treatment with anthracycline-based chemotherapy and/or taxane-based therapy is standard. For patients who respond to neoadjuvant chemotherapy, local therapy may consist of total mastectomy with axillary lymph node dissection followed by postoperative radiation therapy to the chest wall and regional lymphatics. Breast-conserving therapy can be considered in patients with a good partial or complete response to neoadjuvant chemotherapy. Subsequent systemic therapy may consist of further chemotherapy. Hormone therapy should be administered to patients whose tumors are ER-positive or unknown. All patients should be considered candidates for clinical trials to evaluate the most appropriate fashion in which to administer the various components of multimodality regimens.

In one embodiment the combination therapy is administered as part of the various components of multimodality regimens. In another embodiment the combination therapy is administered before, simultaneously with, or after the multimodality regimens. In another embodiment the combination therapy is administered based on synergism between the modalities. In another embodiment the combination therapy is administered after treatment with anthracycline-based chemotherapy and/or taxane-based therapy (Zitvogel et al., 2008). Treatment after administering the combination therapy may negatively affect dividing effector T-cells. The combination therapy may also be administered after radiation.

In another embodiment the combination therapy described herein is used in the treatment in a cancer where the standard of care is primarily not surgery and is primarily based on systemic treatments, such as Chronic Lymphocytic Leukemia (CLL).

In another embodiment patients diagnosed with stage I, II, III, and IV Chronic Lymphocytic Leukemia are treated with the combination therapy as described herein. The standard of care for this cancer type is:

1. Observation in asymptomatic or minimally affected patients

2. Rituximab

3. Ofatumomab

4. Oral alkylating agents with or without corticosteroids

5. Fludarabine, 2-chlorodeoxyadenosine, or pentostatin

6. Bendamustine

7. Lenalidomide

8. Combination chemotherapy.

-   -   combination chemotherapy regimens include the following:         -   Fludarabine plus cyclophosphamide plus rituximab.         -   Fludarabine plus rituximab as seen in the CLB-9712 and             CLB-9011 trials.         -   Fludarabine plus cyclophosphamide versus fludarabine plus             cyclophosphamide plus rituximab.         -   Pentostatin plus cyclophosphamide plus rituximab as seen in             the MAYO-MC0183 trial, for example.         -   Ofatumumab plus fludarabine plus cyclophosphamide.         -   CVP: cyclophosphamide plus vincristine plus prednisone.         -   CHOP: cyclophosphamide plus doxorubicin plus vincristine             plus prednisone.         -   Fludarabine plus cyclophosphamide versus fludarabine as seen             in the E2997 trial [NCT00003764] and the LRF-CLL4 trial, for             example.         -   Fludarabine plus chlorambucil as seen in the CLB-9011 trial,             for example.

9. Involved-field radiation therapy.

10. Alemtuzumab

11. Bone marrow and peripheral stem cell transplantations are under clinical evaluation.

12. Ibrutinib

In one embodiment the combination therapy is administered before, simultaneously with or after treatment with Rituximab or Ofatumomab. As these are monoclonal antibodies that target B-cells, treatment with the combination therapy may be synergistic. In another embodiment the combination therapy is administered after treatment with oral alkylating agents with or without corticosteroids, and Fludarabine, 2-chlorodeoxyadenosine, or pentostatin, as these treatments may negatively affect the immune system if administered before. In one embodiment bendamustine is administered with the combination therapy in low doses based on the results for prostate cancer described herein. In one embodiment the combination therapy is administered after treatment with bendamustine.

In another embodiment, therapies targeted to specific recurrent mutations in genes that include extracellular domains are used in the treatment of a patient in need thereof suffering from cancer. The genes may advantageously be well-expressed genes. Well expressed may be expressed in “transcripts per million” (TPM). A TPM greater than 100 is considered well expressed. Well expressed genes may be FGFR3, ERBB3, EGFR, MUC4, PDGFRA, MMP12, TMEM52, and PODXL. The therapies may be a ligand capable of binding to an extracellular neoantigen epitope. Such ligands are well known in the art and may include therapeutic antibodies or fragments thereof, antibody-drug conjugates, engineered T cells, or aptamers. Engineered T cells may be chimeric antigen receptors (CARs). Antibodies may be fully humanized, humanized, or chimeric. The antibody fragments may be a nanobody, Fab, Fab′, (Fab′)2, Fv, ScFv, diabody, triabody, tetrabody, Bis-scFv, minibody, Fab2, or Fab3 fragment. Antibodies may be developed against tumor-specific neoepitopes using known methods in the art.

Adoptive Cell Transfer (ACT)

Aspects of the invention involve the adoptive transfer of immune system cells, such as T cells, specific for selected antigens, such as tumor associated antigens (see Maus et al., 2014, Adoptive Immunotherapy for Cancer or Viruses, Annual Review of Immunology, Vol. 32: 189-225; Rosenberg and Restifo, 2015, Adoptive cell transfer as personalized immunotherapy for human cancer, Science Vol. 348 no. 6230 pp. 62-68; Restifo et al., 2015, Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 12(4): 269-281; and Jenson and Riddell, 2014, Design and implementation of adoptive therapy with chimeric antigen receptor-modified T cells. Immunol Rev. 257(1): 127-144). Various strategies may for example be employed to genetically modify T cells by altering the specificity of the T cell receptor (TCR) for example by introducing new TCR α and β chains with selected peptide specificity (see U.S. Pat. No. 8,697,854; PCT Patent Publications: WO2003020763, WO2004033685, WO2004044004, WO2005114215, WO2006000830, WO2008038002, WO2008039818, WO2004074322, WO2005113595, WO2006125962, WO2013166321, WO2013039889, WO2014018863, WO2014083173; U.S. Pat. No. 8,088,379).

As an alternative to, or addition to, TCR modifications, chimeric antigen receptors (CARs) may be used in order to generate immunoresponsive cells, such as T cells, specific for selected targets, such as malignant cells, with a wide variety of receptor chimera constructs having been described (see U.S. Pat. Nos. 5,843,728; 5,851,828; 5,912,170; 6,004,811; 6,284,240; 6,392,013; 6,410,014; 6,753,162; 8,211,422; and, PCT Publication WO9215322). Alternative CAR constructs may be characterized as belonging to successive generations. First-generation CARs typically consist of a single-chain variable fragment of an antibody specific for an antigen, for example comprising a V_(L) linked to a V_(H) of a specific antibody, linked by a flexible linker, for example by a CD8α hinge domain and a CD8α transmembrane domain, to the transmembrane and intracellular signaling domains of either CD3ζ or FcRγ (scFv-CD3ζ or scFv-FcRγ; see U.S. Pat. Nos. 7,741,465; 5,912,172; 5,906,936). Second-generation CARs incorporate the intracellular domains of one or more costimulatory molecules, such as CD28, OX40 (CD134), or 4-1BB (CD137) within the endodomain (for example scFv-CD28/OX40/4-1BB-CD3ζ; see U.S. Pat. Nos. 8,911,993; 8,916,381; 8,975,071; 9,101,584; 9,102,760; 9,102,761). Third-generation CARs include a combination of costimulatory endodomains, such a CD3 ζ-chain, CD97, GDI 1a-CD18, CD2, ICOS, CD27, CD154, CDS, OX40, 4-1BB, or CD28 signaling domains (for example scFv-CD28-4-1BB-CD3ζ or scFv-CD28-OX40-CD3 see U.S. Pat. Nos. 8,906,682; 8,399,645; 5,686,281; PCT Publication No. WO2014134165; PCT Publication No. WO2012079000). Alternatively, costimulation may be orchestrated by expressing CARs in antigen-specific T cells, chosen so as to be activated and expanded following engagement of their native αβTCR, for example by antigen on professional antigen-presenting cells, with attendant costimulation. In addition, additional engineered receptors may be provided on the immunoresponsive cells, for example to improve targeting of a T-cell attack and/or minimize side effects.

Alternative techniques may be used to transform target immunoresponsive cells, such as protoplast fusion, lipofection, transfection or electroporation. A wide variety of vectors may be used, such as retroviral vectors, lentiviral vectors, adenoviral vectors, adeno-associated viral vectors, plasmids or transposons, such as a Sleeping Beauty transposon (see U.S. Pat. Nos. 6,489,458; 7,148,203; 7,160,682; 7,985,739; 8,227,432), may be used to introduce CARs, for example using 2nd generation antigen-specific CARs signaling through CD3 and either CD28 or CD137. Viral vectors may for example include vectors based on HIV, SV40, EBV, HSV or BPV.

Cells that are targeted for transformation may for example include T cells, Natural Killer (NK) cells, cytotoxic T lymphocytes (CTL), regulatory T cells, human embryonic stem cells, tumor-infiltrating lymphocytes (TIL) or a pluripotent stem cell from which lymphoid cells may be differentiated. T cells expressing a desired CAR may for example be selected through co-culture with γ-irradiated activating and propagating cells (AaPC), which co-express the cancer antigen and co-stimulatory molecules. The engineered CAR T-cells may be expanded, for example by co-culture on AaPC in presence of soluble factors, such as IL-2 and IL-21. This expansion may for example be carried out so as to provide memory CAR+ T cells (which may for example be assayed by non-enzymatic digital array and/or multi-panel flow cytometry). In this way, CAR T cells may be provided that have specific cytotoxic activity against antigen-bearing tumors (optionally in conjunction with production of desired chemokines such as interferon-γ). CAR T cells of this kind may for example be used in animal models, for example to treat tumor xenografts.

Approaches such as the foregoing may be adapted to provide methods of treating and/or increasing survival of a subject having a disease, such as a neoplasia, for example by administering an effective amount of an immunoresponsive cell comprising an antigen recognizing receptor that binds a selected antigen, wherein the binding activates the immunoreponsive cell, thereby treating or preventing the disease (such as a neoplasia, a pathogen infection, an autoimmune disorder, or an allogeneic transplant reaction).

In one embodiment, the treatment can be administrated into patients undergoing an immunosuppressive treatment. The cells or population of cells, may be made resistant to at least one immunosuppressive agent due to the inactivation of a gene encoding a receptor for such immunosuppressive agent. Not being bound by a theory, the immunosuppressive treatment should help the selection and expansion of the immunoresponsive or T cells according to the invention within the patient.

The administration of the cells or population of cells according to the present invention may be carried out in any convenient manner, including by aerosol inhalation, injection, ingestion, transfusion, implantation or transplantation. The cells or population of cells may be administered to a patient subcutaneously, intradermally, intratumorally, intranodally, intramedullary, intramuscularly, by intravenous or intralymphatic injection, or intraperitoneally. In one embodiment, the cell compositions of the present invention are preferably administered by intravenous injection.

The administration of the cells or population of cells can consist of the administration of 10⁴-10⁹ cells per kg body weight, preferably 10⁵ to 10⁶ cells/kg body weight including all integer values of cell numbers within those ranges. Dosing in CAR T cell therapies may for example involve administration of from 10⁶ to 10⁹ cells/kg, with or without a course of lymphodepletion, for example with cyclophosphamide. The cells or population of cells can be administrated in one or more doses. In another embodiment, the effective amount of cells are administrated as a single dose. In another embodiment, the effective amount of cells are administrated as more than one dose over a period time. Timing of administration is within the judgment of managing physician and depends on the clinical condition of the patient. The cells or population of cells may be obtained from any source, such as a blood bank or a donor. While individual needs vary, determination of optimal ranges of effective amounts of a given cell type for a particular disease or conditions are within the skill of one in the art. An effective amount means an amount which provides a therapeutic or prophylactic benefit. The dosage administrated will be dependent upon the age, health and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired.

In another embodiment, the effective amount of cells or composition comprising those cells are administrated parenterally. The administration can be an intravenous administration. The administration can be directly done by injection within a tumor.

To guard against possible adverse reactions, engineered immunoresponsive cells may be equipped with a transgenic safety switch, in the form of a transgene that renders the cells vulnerable to exposure to a specific signal. For example, the herpes simplex viral thymidine kinase (TK) gene may be used in this way, for example by introduction into allogeneic T lymphocytes used as donor lymphocyte infusions following stem cell transplantation (Greco, et al., Improving the safety of cell therapy with the TK-suicide gene. Front. Pharmacol. 2015; 6: 95). In such cells, administration of a nucleoside prodrug such as ganciclovir or acyclovir causes cell death. Alternative safety switch constructs include inducible caspase 9, for example triggered by administration of a small-molecule dimerizer that brings together two nonfunctional icasp9 molecules to form the active enzyme. A wide variety of alternative approaches to implementing cellular proliferation controls have been described (see U.S. Patent Publication No. 20130071414; PCT Patent Publication WO2011146862; PCT Patent Publication WO2014011987; PCT Patent Publication WO2013040371; Zhou et al. BLOOD, 2014, 123/25:3895-3905; Di Stasi et al., The New England Journal of Medicine 2011; 365:1673-1683; Sadelain M, The New England Journal of Medicine 2011; 365:1735-173; Ramos et al., Stem Cells 28(6): 1107-15 (2010)).

In a further refinement of adoptive therapies, genome editing may be used to tailor immunoresponsive cells to alternative implementations, for example providing edited CAR T cells (see Poirot et al., 2015, Multiplex genome edited T-cell manufacturing platform for “off-the-shelf” adoptive T-cell immunotherapies, Cancer Res 75 (18): 3853). Cells may be edited using any DNA targeting protein, including, but not limited to a CRISPR system, Zinc Finger binding protein, TALE or TALEN as known in the art. DNA targeting proteins may be delivered to an immune cell by any method known in the art. In preferred embodiments, cells are edited ex vivo and transferred to a subject in need thereof. Immunoresponsive cells, CAR T cells or any cells used for adoptive cell transfer may be edited. Editing may be performed to eliminate potential alloreactive T-cell receptors (TCR), disrupt the target of a chemotherapeutic agent, block an immune checkpoint, activate a T cell, and/or increase the differentiation and/or proliferation of functionally exhausted or dysfunctional CD8+ T-cells (see PCT Patent Publications: WO2013176915, WO2014059173, WO2014172606, WO2014184744, and WO2014191128). Editing may result in inactivation of a gene.

By inactivating a gene it is intended that the gene of interest is not expressed in a functional protein form. In a particular embodiment, the CRISPR system specifically catalyzes cleavage in one targeted gene thereby inactivating said targeted gene. The nucleic acid strand breaks caused are commonly repaired through the distinct mechanisms of homologous recombination or non-homologous end joining (NHEJ). However, NHEJ is an imperfect repair process that often results in changes to the DNA sequence at the site of the cleavage. Repair via non-homologous end joining (NHEJ) often results in small insertions or deletions (Indel) and can be used for the creation of specific gene knockouts. Cells in which a cleavage induced mutagenesis event has occurred can be identified and/or selected by well-known methods in the art.

T cell receptors (TCR) are cell surface receptors that participate in the activation of T cells in response to the presentation of antigen. The TCR is generally made from two chains, α and β, which assemble to form a heterodimer and associates with the CD3-transducing subunits to form the T cell receptor complex present on the cell surface. Each α and β chain of the TCR consists of an immunoglobulin-like N-terminal variable (V) and constant (C) region, a hydrophobic transmembrane domain, and a short cytoplasmic region. As for immunoglobulin molecules, the variable region of the α and β chains are generated by V(D)J recombination, creating a large diversity of antigen specificities within the population of T cells. However, in contrast to immunoglobulins that recognize intact antigen, T cells are activated by processed peptide fragments in association with an MHC molecule, introducing an extra dimension to antigen recognition by T cells, known as MHC restriction. Recognition of MHC disparities between the donor and recipient through the T cell receptor leads to T cell proliferation and the potential development of graft versus host disease (GVHD). The inactivation of TCRα or TCRβ can result in the elimination of the TCR from the surface of T cells preventing recognition of alloantigen and thus GVHD. However, TCR disruption generally results in the elimination of the CD3 signaling component and alters the means of further T cell expansion.

Allogeneic cells are rapidly rejected by the host immune system. It has been demonstrated that, allogeneic leukocytes present in non-irradiated blood products will persist for no more than 5 to 6 days (Boni, Muranski et al. 2008 Blood 1; 112(12):4746-54). Thus, to prevent rejection of allogeneic cells, the host's immune system usually has to be suppressed to some extent. However, in the case of adoptive cell transfer the use of immunosuppressive drugs also have a detrimental effect on the introduced therapeutic T cells. Therefore, to effectively use an adoptive immunotherapy approach in these conditions, the introduced cells would need to be resistant to the immunosuppressive treatment. Thus, in a particular embodiment, the present invention further comprises a step of modifying T cells to make them resistant to an immunosuppressive agent, preferably by inactivating at least one gene encoding a target for an immunosuppressive agent. An immunosuppressive agent is an agent that suppresses immune function by one of several mechanisms of action. An immunosuppressive agent can be, but is not limited to a calcineurin inhibitor, a target of rapamycin, an interleukin-2 receptor α-chain blocker, an inhibitor of inosine monophosphate dehydrogenase, an inhibitor of dihydrofolic acid reductase, a corticosteroid or an immunosuppressive antimetabolite. The present invention allows conferring immunosuppressive resistance to T cells for immunotherapy by inactivating the target of the immunosuppressive agent in T cells. As non-limiting examples, targets for an immunosuppressive agent can be a receptor for an immunosuppressive agent such as: CD52, glucocorticoid receptor (GR), a FKBP family gene member and a cyclophilin family gene member.

Immune checkpoints are inhibitory pathways that slow down or stop immune reactions and prevent excessive tissue damage from uncontrolled activity of immune cells. In certain embodiments, the immune checkpoint targeted is the programmed death-1 (PD-1 or CD279) gene (PDICDI). In other embodiments, the immune checkpoint targeted is cytotoxic T-lymphocyte-associated antigen (CTLA-4). In additional embodiments, the immune checkpoint targeted is another member of the CD28 and CTLA4 Ig superfamily such as BTLA, LAG3, ICOS, PDL1 or KIR. In further additional embodiments, the immune checkpoint targeted is a member of the TNFR superfamily such as CD40, OX40, CD137, GITR, CD27 or TIM-3.

Additional immune checkpoints include Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) (Watson H A, et al., SHP-1: the next checkpoint target for cancer immunotherapy? Biochem Soc Trans. 2016 Apr. 15; 44(2):356-62). SHP-1 is a widely expressed inhibitory protein tyrosine phosphatase (PTP). In T-cells, it is a negative regulator of antigen-dependent activation and proliferation. It is a cytosolic protein, and therefore not amenable to antibody-mediated therapies, but its role in activation and proliferation makes it an attractive target for genetic manipulation in adoptive transfer strategies, such as chimeric antigen receptor (CAR) T cells. Immune checkpoints may also include T cell immunoreceptor with Ig and ITIM domains (TIGIT/Vstm3/WUCAM/VSIG9) and VISTA (Le Mercier I, et al., (2015) Beyond CTLA-4 and PD-1, the generation Z of negative checkpoint regulators. Front. Immunol. 6:418).

WO2014172606 relates to the use of MT1 and/or MT1 inhibitors to increase proliferation and/or activity of exhausted CD8+ T-cells and to decrease CD8+ T-cell exhaustion (e.g., decrease functionally exhausted or unresponsive CD8+ immune cells). In certain embodiments, metallothioneins are targeted by gene editing in adoptively transferred T cells.

In certain embodiments, targets of gene editing may be at least one targeted locus involved in the expression of an immune checkpoint protein. Such targets may include, but are not limited to CTLA4, PPP2CA, PPP2CB, PTPN6, PTPN22, PDCD1, ICOS (CD278), PDL1, KIR, LAG3, HAVCR2, BTLA, CD160, TIGIT, CD96, CRTAM, LAIR1, SIGLEC7, SIGLEC9, CD244 (2B4), TNFRSF10B, TNFRSF10A, CASP8, CASP10, CASP3, CASP6, CASP7, FADD, FAS, TGFBRII, TGFRBRI, SMAD2, SMAD3, SMAD4, SMAD10, SKI, SKIL, TGIF1, IL10RA, IL10RB, HMOX2, IL6R, IL6ST, EIF2AK4, CSK, PAG1, SIT1, FOXP3, PRDM1, BATF, VISTA, GUCY1A2, GUCY1A3, GUCY1B2, GUCY1B3, MT1, MT2, CD40, OX40, CD137, GITR, CD27, SHP-1 or TIM-3. In preferred embodiments, the gene locus involved in the expression of PD-1 or CTLA-4 genes is targeted. In other preferred embodiments, combinations of genes are targeted, such as but not limited to PD-1 and TIGIT.

In other embodiments, at least two genes are edited. Pairs of genes may include, but are not limited to PD1 and TCRα, PD1 and TCRβ, CTLA-4 and TCRα, CTLA-4 and TCRβ, LAG3 and TCRα, LAG3 and TCRβ, Tim3 and TCRα, Tim3 and TCRβ, BTLA and TCRα, BTLA and TCRβ, BY55 and TCRα, BY55 and TCRβ3, TIGIT and TCRα, TIGIT and TCRβ, B7H5 and TCRα, B7H5 and TCRβ, LAIR1 and TCRα, LAIR1 and TCRβ, SIGLEC10 and TCRα, SIGLEC10 and TCRβ, 2B4 and TCRα, 2B4 and TCRβ3.

Whether prior to or after genetic modification of the T cells, the T cells can be activated and expanded generally using methods as described, for example, in U.S. Pat. Nos. 6,352,694; 6,534,055; 6,905,680; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,232,566; 7,175,843; 5,883,223; 6,905,874; 6,797,514; 6,867,041; and 7,572,631. T cells can be expanded in vitro or in vivo.

Selecting the Patient Population Most Likely to Benefit from the Therapy

In another aspect, the invention provides selecting for the patients in need thereof most likely to benefit from the therapy of the present invention. Although the compositions and methods of the present invention are typically applicable in a high proportion of subjects suffering from cancer, the method may still comprise one or more steps of selecting patients from the patient population who are likely to benefit. For instance, the method may comprise selecting subjects whose tumors contain one or more of the mutations represented in the neoantigenic peptides in the composition. In another embodiment, the method may comprise selecting subjects having at least one HLA allele which binds to one or more neoepitopes represented in the neoantigenic peptides in the composition.

Vaccine or Immunogenic Composition Kits and Co-Packaging

In an aspect, the invention provides kits containing any one or more of the elements discussed herein to allow administration of the therapy. Elements may be provided individually or in combinations, and may be provided in any suitable container, such as a vial, a bottle, or a tube. In some embodiments, the kit includes instructions in one or more languages, for example in more than one language. In some embodiments, a kit comprises one or more reagents for use in a process utilizing one or more of the elements described herein. Reagents may be provided in any suitable container. For example, a kit may provide one or more delivery or storage buffers. Reagents may be provided in a form that is usable in a particular process, or in a form that requires addition of one or more other components before use (e.g. in concentrate or lyophilized form). A buffer can be any buffer, including but not limited to a sodium carbonate buffer, a sodium bicarbonate buffer, a borate buffer, a Tris buffer, a MOPS buffer, a HEPES buffer, and combinations thereof. In some embodiments, the buffer is alkaline. In some embodiments, the buffer has a pH from about 7 to about 10. In some embodiments, the kit comprises one or more of the vectors, proteins and/or one or more of the polynucleotides described herein. The kit may advantageously allow the provision of all elements of the systems of the invention. Kits can involve vector(s) and/or particle(s) and/or nanoparticle(s) containing or encoding RNA(s) for 1-50 or more neoantigen mutations to be administered to an animal, mammal, primate, rodent, etc., with such a kit including instructions for administering to such a eukaryote; and such a kit can optionally include any of the anti-cancer agents described herein. The kit may include any of the components above (e.g. vector(s) and/or particle(s) and/or nanoparticle(s) containing or encoding RNA(s) for 1-50 or more neoantigen mutations, neoantigen proteins or peptides) as well as instructions for use with any of the methods of the present invention.

In one embodiment the kit contains at least one vial with an immunogenic composition or vaccine. In one embodiment the kit contains at least one vial with an immunogenic composition or vaccine and at least one vial with an anticancer agent. In one embodiment kits may comprise ready to use components that are mixed and ready to administer. In one aspect a kit contains a ready to use immunogenic or vaccine composition and a ready to use anti-cancer agent. The ready to use immunogenic or vaccine composition may comprise separate vials containing different pools of immunogenic compositions. The immunogenic compositions may comprise one vial containing a viral vector or DNA plasmid and the other vial may comprise immunogenic protein. The ready to use anticancer agent may comprise a cocktail of anticancer agents or a single anticancer agent. Separate vials may contain different anti-cancer agents. In another embodiment a kit may contain a ready to use anti-cancer agent and an immunogenic composition or vaccine in a ready to be reconstituted form. The immunogenic or vaccine composition may be freeze dried or lyophilized. The kit may comprise a separate vial with a reconstitution buffer that can be added to the lyophilized composition so that it is ready to administer. The buffer may advantageously comprise an adjuvant or emulsion according to the present invention. In another embodiment the kit may comprise a ready to reconstitute anti-cancer agent and a ready to reconstitute immunogenic composition or vaccine. In this aspect both may be lyophilized. In this aspect separate reconstitution buffers for each may be included in the kit. The buffer may advantageously comprise an adjuvant or emulsion according to the present invention. In another embodiment the kit may comprise single vials containing a dose of immunogenic composition and anti-cancer agent that are administered together. In another aspect multiple vials are included so that one vial is administered according to a treatment timeline. One vial may only contain the anti-cancer agent for one dose of treatment, another may contain both the anti-cancer agent and immunogenic composition for another dose of treatment, and one vial may only contain the immunogenic composition for yet another dose. In a further aspect the vials are labeled for their proper administration to a patient in need thereof. The immunogen or anti-cancer agents of any embodiment may be in a lyophilized form, a dried form or in aqueous solution as described herein. The immunogen may be a live attenuated virus, protein, or nucleic acid as described herein.

In one embodiment the anticancer agent is one that enhances the immune system to enhance the effectiveness of the immunogenic composition or vaccine. In a preferred embodiment the anti-cancer agent is a checkpoint inhibitor. In another embodiment the kit contains multiple vials of immunogenic compositions and anti-cancer agents to be administered at different time intervals along a treatment plan. In another embodiment the kit may comprise separate vials for an immunogenic composition for use in priming an immune response and another immunogenic composition to be used for boosting. In one aspect the priming immunogenic composition could be DNA or a viral vector and the boosting immunogenic composition may be protein. Either composition may be lyophilized or ready for administering. In another embodiment different cocktails of anti-cancer agents containing at least one anti-cancer agent are included in different vials for administration in a treatment plan.

Although the present invention and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined in the appended claims.

The present invention will be further illustrated in the following Examples which are given for illustration purposes only and are not intended to limit the invention in any way.

EXAMPLES Example 1

sPDL1 Generates Immunogenic Epitopes Across a Variety of HLA Alleles.

PDL1 (CD274) is a trans-membrane protein which interacts with PD1 (CD279; PDCD1) on T cells and may be involved in multiple forms of natural immune suppression (such as during gestation). Expression of PDL1 is also utilized by tumor cells as a way to evade host immune response. sPDL1 is an alternate spliced form of the PDL1 gene. This alternate spliced form is caused by a lack of splicing at the end of Exon 4, reading into the 4^(th) intron. The transcript terminates within intron 4. The translation product is in frame for 18 amino acids before a stop codon is encountered.

The translated product lacks the transmembrane domain typically found in PDL1 and thus is secreted. It also contains a cysteine within the neoORF translated from the intron and appears to dimerize in the media. The secreted form appears to block binding between PDL1 and PD1.

Applicants analyzed the predicted binding possibilities for 9 and 10mer peptides containing the neoORF region encoded by the intron. The analysis is shown for predicted 9mer peptides Table 1. The values in bolded font are alleles that are present at a frequency >5% in the indicated population. Notably, the common HLA allele A0210 in the Caucasian population is predicted to have a reasonably tight binding peptide. A similar analysis shows that 10mer peptides are also predicted to be potentially immunogenic, including for the A0201 allele (85 nM). Tumor cells expressing the alternate form of the PDL1 message would be thus rendered as targets of the immune system.

These peptides could be utilized across multiple patients (either HLA-restricted or more broadly if the patient is expected to have some probability to contain a relevant HLA allele) as a “Shared Neoantigen”. Note that given the relatively short size of the neoORF region of sPDL1, two or three long overlapping peptides could be used as a mixture, allowing targeting of any HLA allele, even rare alleles, and reducing the need to prepare a different product for each patient based on their HLA type.

This neoORF may also contain a CD4 epitope although prediction algorithms for CD4 epitopes are not highly accurate. The presence of a CD4 epitope could be assessed in vitro with naive T cells or in patient samples.

TABLE 1 (SEQ ID NOS 1-23, respectively, in order of appearance) affinity ENHTAELVIP HLA peptide 9mers (nM) Caucasian Black Asian Hispanic GNILNVSIKICLTLSPST A0201 VIPGNILNV 182 28.3%  11.4% 9.7% 19.7% B4001 AELVIPGNI 144 4.0% 1.0% 12.0% 1.3% A3201 NILNVSIKI 491 3.2% 1.6% 0.3% 2.6% A3201 VSIKICLTL 224 3.2% 1.6% 0.3% 2.6% A2301 VSIKICLTL 468 2.3% 11.6% 0.2% 3.5% B4002 AELVIPGNI 53 1.6% 0.3% 7.6% 5.0% B4901 AELVIPGNI 108 1.4% 3.1% 0.0% 2.3% B4102 AELVIPGNI 192 1.0% 0.6% 0.0% 0.5% A0205 VIPGNILNV 170 0.8% 2.3% 0.1% 1.4% B5801 VSIKICLTL 373 0.8% 4.3% 4.5% 1.3% A6802 HTAEVIPG 170 0.7% 6.4% 0.0% 2.4% B4405 AELVIPGNI 219 0.6% 0.0% 0.0% 0.2% B4101 AELVIPGNI 92 0.5% 0.6% 0.0% 1.1% B4501 AELVIPGNI 302 0.4% 5.3% 0.0% 1.5% B1517 VSIKICLTL 23 0.3% 0.5% 0.1% 0.6% A0206 VIPGNILNV 85 0.2% 0.0% 4.7% 4.1% A0202 VIPGNILNV 90 0.1% 4.4% 0.0% 0.7% A6901 HTAEVIPG 283 0.1% 0.1% 0.0% 0.5% A6901 NILNVSIKI 162 0.1% 0.1% 0.0% 0.5% B1503 IKICLTLSP 408 0.1% 6.5% 0.1% 1.5% B1503 VSIKICLTL 138 0.1% 6.5% 0.1% 1.5% A0203 VIPGNILNV 98 0.0% 0.0% 5.2% 0.0%

Example 2

Androgen Receptor Generates Immunogenic Epitopes Across a Variety of HLA Alleles.

The androgen receptor was identified as another alternate spliced form of a message that results in a neoORF which may be specifically expressed in tumor cells. Alternate splicing results in at least two isoforms that bring in cryptic exons that are .neoORFs.

Of these alternate transcripts, AR-V1 and AR-V7 were consistently seen in hormone resistant prostate cancer samples.

The immunogenic potential of these neoORFs was unknown and thus Applicants conducted predicted binding analysis across a number of common HLA alleles. These are shown for HLA A alleles (Table 2).

TABLE 2 (SEQ ID NOS 24, 27, 28, 30, 25. 29, 31, 26, 32, 33, 41, 43, 45, 34, 42. 44, 46, 35, 47,36, 48.37, 49 and 38-40, respectively, in order of appearance) A0201 A0301 A1101 A3001 Caucasian 28.30% 13.70%  6.00% 1.60% Asian  9.70% 0.90% 22.40%  1.40% Hispanic 19.65% 7.59% 4.88% 2.20% Black 11.40% 7.10% 1.00% 6.50% RVFG SEQ2 233 RVGNC SEQ1 122 RVGNC SEQ1  33 RVGN SEQ1  30 VSEWL KHLK KHLK CKHLK GMTLG SEQ2 282 VVVS SEQ2 359 KFRV SEQ1 103 AVVV ERILR GNCKH MTLGE SEQ1 400 KFRVG SEQ1 190 KFRV NCKHL A3101 A3201 A3301 A6801 A B 2.40% 3.20% 0.70% 3.40% 30.30% 6.80% Caucasian 3.40% 0.30% 0.60% 0.30% 28.70% 19.70%  Asian 4.72% 2.62% 1.97% 4.46% 26.46% 7.86% Hispanic 1.00% 1.60% 1.70% 3.20% 20.40% 2.10% Black RVGN SEQ1  70 RVFG SEQ2  41 NCK SEQ1 385 VVVS SEQ2  47 CKHLK VSEWL HLK ERILR MTR TLGAV SEQ2 121 ILRVF SEQ2 255 TLG SEQ2 417 TLGA SEQ2  84 VVSER GVSEW AVV VVVS VSER ER VVVS SEQ2 127 EAGM SEQ 1 230 ERILR TLGEK GMTL SEQ1 199 LGAV SEQ2 268 GEKFR VVSER AVVV SEQ2 230 AVVV SEQ2 339 SERILR SERILR AGMTL SEQ1 284 GEKFR GNCKHL SEQ1 466 KMTR LGAV SEQ2 488 VVSER

Again, as for sPDL1, a number of peptides are predicted to be immunogenic binders and these can be applied across a large subset of patients. These immunogenic peptides can be used across multiple patients.

Example 3

Drug Resistant Mutations.

Treatment with various chemotherapeutic agents, particularly with targeted therapies such as tyrosine kinase inhibitors, frequently leads to new mutations in the target molecules that resist the activity of the therapeutic. Multiple strategies to overcome this resistance are being evaluated, including development of second generation therapies that are not affected by these mutations and treatment with multiple agents including those that act downstream of the resistance mutation.

Applicants have evaluated the immunogenic potential of the mutated peptides created by these resistance mutations and have found that for some, predicted immunogenic peptides are created that can bind to a range of HLA alleles. Two specific examples are provided below as well as data for a range of resistance variants.

BTK/C481S

A very common mutation to ibrutinib, a molecule targeting Bruton's Tyrosine Kinase (BTK) and used for CLL and certain lymphomas, is a Cysteine to Serine change at position 481. This change produces a number of binding peptides which bind to a range of HLA molecules.

Shown are results of binding predictions for 9mer peptides. Similar binding peptides can be found for 10mer peptides (Table 3). Only peptides with mutant predicted affinity below 150 nM are included. Expanding the range of peptides up to 500 nM would also significantly increase the number of HLA range.

TABLE 3 (SEQ ID NOS 50-72, respectively, in order of appearance) HLA peptide 9mers Affinity (nM) MUT Affinity (nM) NAT Caucasian Black Asian Hispanic A0201 SLLNYLREM 97 278 28.3% 11.4% 9.7% 19.7% A2402 EYMANGSLL 95 120 9.3% 2.0% 23.1% 12.4% B1801 TEYMANGSL 80 252 6.1% 3.5% 0.4% 4.1% B1501 MANGSLLNY 91 158 5.8% 0.8% 12.1% 2.6% B3501 MANGSLLNY 17 17 5.6% 6.1% 2.4% 6.0% B4001 TEYMANGSL 10 24 4.0% 1.0% 12.0% 1.3% A3101 LLNYLREMR 43 206 2.4% 1.0% 3.4% 4.7% A2301 EYMANGSLL 122 133 2.3% 11.6% 0.2% 3.5% A2902 MANGSLLNY 17 10 2.0% 4.4% 0.0% 4.1% B4002 TEYMANGSL 45 110 1.6% 0.3% 7.6% 5.0% B4102 TEYMANGSL 133 341 1.0% 0.6% 0.0% 0.5% B5801 MANGSLLNY 40 35 0.8% 4.3% 4.5% 1.3% A3301 LLNYLREMR 91 188 0.7% 1.7% 0.6% 2.0% A3002 MANGSLLNY 16 15 0.5% 6.6% 0.0% 2.8% A6804 EYMANGSLL 47 448 0.0% 0.0% 0.0% 0.0% B1801 TEYMANGSL 44 252 6.1% 3.5% 0.4% 4.1% B1501 MANGSLLNY 42 158 5.8% 0.8% 12.1% 2.6% B3501 MANGSLLNY 40 17 5.6% 6.1% 2.4% 6.0% B4001 TEYMANGSL 38 24 4.0% 1.0% 12.0% 1.3% A3101 LLNYLREMR 36 206 2.4% 1.0% 3.4% 4.7% A2301 EYMANGSLL 34 133 2.3% 11.6% 0.2% 3.5% A2902 MANGSLLNY 32 10 2.0% 4.4% 0.0% 4.1% B4002 TEYMANGSL 30 110 1.6% 0.3% 7.6% 5.0%

Such peptide immunogens are preferably utilized prophylactically (prior to detection of resistant disease) to induce an immunogenic response capable of killing any pre-existing or newly mutated cells or could also be used at the time of detection of disease recurrence following or during therapy. These peptides could be utilized across multiple patients (either HLA-restricted or more broadly if the patient is expected with some probability to contain a relevant HLA allele).

EGFR/T790M

Erlotinib, which targets the tyrosine kinase domain of the Epidermal Growth Factor Receptor (EGFR), is commonly used in the treatment of lung cancer and resistant tumors invariably develop following therapy. A common mutation found in resistant clones is a Threonine to methionine mutation at position 790. This change produces a number of binding peptides which bind to a range of HLA molecules (Table 4).

TABLE 4 SUM Caucasian  2.3%  3.9% 4.0% 3.2% 3.2% 17% Black 11.6%  0.3% 1.5% 1.6% 1.6% 17% Asian  0.2%    0.0% 3.9% 0.3% 0.3%  5% Hispanic  3.5%  0.9% 2.8% 2.6% 2.6% 12% A23C1 A2501 A2601 A3201 A3201 VQLIMQLMPF 366 STVQLIMQLM 125 STVQLIMQLM 67 QLIMQLMPF 155 QLIMQLMPF 155 VQLIMQLMPF 426 VQLIMQLMPF 426 Caucasian  4.2%  5.8% 2.9% 1.4% 0.4% 1.6% 16% Black  1.2%  0.8% 0.1% 0.3% 0.1% 0.3%  3% Asian  1.2% 12.1% 0.2% 2.4% 0.0% 7.6% 24% Hispanic  1.2%  2.6% 1.8% 1.0% 2.2% 5.0% 14% B1302 B1501 B3801 B3901 B3906 B4002 MQLMPFGCLL 125 MQLMPFGCLL 488 MQLMPFGCLL 400 MQLMPFGCLL 213 MQLMPFGCLL 400 MQLMPFGCL 221 QLIMQLMPF     23 MQLMPFGCLL 103 VQLIMQLMPF  73 VQLIMQLMPF 365 (SEQ ID NOS 73,74,74-76,73,73,78,78,78,78,78,79,80,78,77 and 77, respectively, in order of apperance)

As stated herein, such peptide immunogens are ideally utilized prophylactically (prior to detection of resistant disease) to induce an immunogenic response capable of killing any pre-existing or newly mutated cells or are also used at the time of detection of disease recurrence following or during therapy. These peptides could be utilized across multiple patients (either HLA-restricted or more broadly if the patient is expected with some probability to contain a relevant HLA allele).

Note that as an immunogen, only a single long peptide containing the mutated amino acid and at least 10 amino acids on either side of the mutated amino acid would be sufficient to contain all the epitopes listed. Thus, all the HLA alleles shown, as well as any additional alleles that have not been shown in this analysis would be covered. For the Caucasian population, the HLA A alleles shown represent 17% of the population distribution of alleles and the HLA B alleles represent 16% of the population distribution of alleles. As each individual has two HLA A alleles and two HLA B alleles, approximately 50% of Caucasian patients will be expected to have at least one of the alleles shown and thus benefit from immune therapy with a vaccine targeting this molecule. This rationale also applies to any other single amino acid mutation discussed herein.

Other Resistance Variants

In addition to the specific resistance cases discussed herein, there are many other observed resistance mutations to targeted therapy. Each of these are also used to define immunogenic epitopes that could be utilized as vaccine for immunotherapy targeting those cells containing the resistance mutations (Table 5).

TABLE 5 Resistance Drug Gene mutation Sensitive Refs Imatinib BCR-Abl T315I http://www.mycancergenome.org/content/disease/chronic-myeloid-leukemia/ Imatinib BCR-Abl Y253H http://www.mycancergenome.org/content/disease/chronic-myeloid-leukemia/ Imatinib BCR-Abl E255K http://www.mycancergenome.org/content/disease/chronic-myeloid-leukemia/ Imatinib BCR-Abl E255V http://www.mycancergenome.org/content/disease/chronic-myeloid-leukemia/ Imatinib c-kit T670I http://www.mycancergenome.org/content/disease/gist/kit/50/ Erlotinib/gefitinib PIK3CA E545K PMC1570180; PMC3132801 Erlotinib/gefitinib HER2 G776(YVMA) PMID 16843263; 15753357 Erlotinib/gefitinib EML4-ALK G1269A http://www.ncbi.nlm.nih.gov/pubmed/22235099?dopt=Abstract Crizotinib KRAS G12V/D http://www.ncbi.nlm.nih.gov/pubmed/22235099?dopt=Abstract Crizotinib ALK L1196M http://stm.sciencemag.org/content/4/120/120ra17 Crizotinib ALK G1202R http://stm.sciencemag.org/content/4/120/120ra17 Crizotinib ALK S1206Y http://stm.sciencemag.org/content/4/120/120ra17 Crizotinib ALK 1151T(ins) http://stm.sciencemag.org/content/4/120/120ra17 Crizotinib ALK F1174C http://cancerdiscovery.aacrjournals.org/content/4/6/662 Crizotinib ROS1 G2032R http://www.nejm.org/doi/full/10.1056/NEJMoa1215530 Crizotinib PIK3CA E542K http://www.mycancergenome.org/content/disease/breast-cancer/ Trastuzumab Her2 E545K http://www.mycancergenome.org/content/disease/breast-cancer/ Trastuzumab Hwe2 H1047R http://www.mycancergenome.org/content/disease/breast-cancer/ Trastuzumab AKT1 E17K http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834432/ Trastuzumab BRAF V600E Vemurafenib MEK1 Q56P http://www.ncbi.nlm.nih.gov/pubmed/23569304 Vemurafenib MEK1 E203K http://www.ncbi.nlm.nih.gov/pubmed/23569304 Vemurafenib MEK1 C121S http://cancerdiscovery.aacrjournals.org/content/4/1/94.long Vemurafenib NRAS Q61K/L http://www/ncbi.nlm.nih.gov/pubmed/23569304 Vemurafenib NRAS Q61R http://cancerdiscovery.aacrjournals.org/content/4/1/94.long Vemurafenib NRAS T58I http://cancerdiscovery.aacrjournals.org/content/4/1/94.long Vemurafenib MEK2 C125S http://cancerdiscovery.aacrjournals.org/content/4/1/94.long Vemurafenib MEK1 V60E http://cancerdiscovery.aacrjournals.org/content/4/1/94.long RAF/MEK MEK1 G128V http://cancerdiscovery.aacrjournals.org/content/4/1/94.long RAF/MEK MEK1 V154I http://cancerdiscovery.aacrjournals.org/content/4/1/94.long RAF/MEK MEK1 P124S http://cancerdiscovery.aacrjournals.org/content/4/1/94.long RAF/MEK MEK1 P124L http://cancerdiscovery.aacrjournals.org/content/4/1/94.long RAF/MEK RAC1 P29S http://cancerdiscovery.aacrjournals.org/content/4/1/94.long RAF/MEK ESR1 S463P http://cancerdiscovery.aacrjournals.org/content/4/1/94.long Antiestrogen AR V534E http://www.mycancergenome.org/content/disease/breast-cancer/er/314/ therapy Antiestrogen AR P535H http://www.mycancergenome.org/content/disease/breast-cancer/er/314/ therapy Antiestrogen AR L536Q http://www.mycancergenome.org/content/disease/breast-cancer/er/314/ therapy Antiestrogen AR L536R http://www.mycancergenome.org/content/disease/breast-cancer/er/314/ therapy Antiestrogen AR Y537C http://www.mycancergenome.org/content/disease/breast-cancer/er/314/ therapy Antiestrogen AR Y537S http://www.mycancergenome.org/content/disease/breast-cancer/er/314/ therapy Antiestrogen AR Y537N http://www.mycancergenome.org/content/disease/breast-cancer/er/314/ therapy Antiestrogen AR D538G http://www.mycancergenome.org/content/disease/breast-cancer/er/314/ therapy Antiestrogen AR F876L http://cancerdiscovery.aacrjournals.org/content/early/2013/06/18/2159-8290.CD-13-0226 therapy

A number of these examples have been used to predict immunogenic epitopes. These results are summarized in Table 6, in which for each resistance mutation, the number of potential binding peptides (with predicted affinity <500 nM) for each mutation are shown for multiple Human HLA alleles.

TABLE 6 ABL1:pT315I ALK:p.F1174C ALK:p.F1174L ALK:p.G1202R ALK:p.G1269A ALK:p.L1196M ALK:p.S1206Y AR:p.F876L RES 500 Caucasian Black Asian 80 80 80 80 80 80 80 80 hla_a_01_01 0.143 0.047 0.012 1 hla_a_02_01 0.283 0.114 0.097 1 2 hla_a_02_03 0 0 0.052 1 2 2 hla_a_02_07 0 0 0.08 1 hla_a_03_01 0.137 0.071 0.009 1 1 hla_a_11_01 0.06 0.01 0.224 1 1 2 hla_a_23_01 0.023 0.116 0.002 2 hla_a_24_02 0.093 0.02 0.231 1 hla_a_30_01 0.016 0.065 0.014 1 1 2 1 1 1 hla_a_30_02 0.005 0.066 0 2 2 hla_a_33_03 0.004 0.041 0.072 3 1 3 hla_a_68_02 0.007 0.064 0 hla_a_74_01 0 0.051 0.001 1 1 1 hla_b_07_02 0.118 0.062 0.015 2 1 hla_b_08_01 0.098 0.039 0.002 1 hla_b_15_01 0.058 0.008 0.121 1 1 3 1 hla_b_15_02 0 0 0.066 1 2 3 1 hla_b_15_03 0.001 0.065 0.001 5 3 3 2 4 4 4 hla_b_18_01 0.061 0.035 0.004 2 1 1 1 hla_b_35_01 0.056 0.061 0.024 3 1 1 2 2 hla_b_40_01 0.04 0.01 0.12 3 1 1 1 1 hla_b_40_02 0.016 0.003 0.076 3 1 1 1 1 1 2 hla_b_42_01 0 0.057 0 2 hla_b_44_02 0.071 0.014 0.002 1 1 hla_b_45_01 0.004 0.053 0 1 1 hla_b_46_01 0 0 0.082 1 hla_b_51_01 0.051 0.021 0.04 2 hla_b_53_01 0.003 0.11 0 1 1 BTK:p.C481S EGFR:p.T790M KRAS:p.G12D MAP2K1:p.C121S MAP2K1:p.E203K MAP2K1:p.G128V MAP2K1:p.P124L MAP2K1:p.P124S RES 500 Caucasian Black Asian 80 80 80 80 80 80 80 80 hla_a_01_01 0.143 0.047 0.012 2 1 1 2 hla_a_02_01 0.283 0.114 0.097 1 2 1 1 3 2 1 hla_a_02_03 0 0 0.052 2 1 2 1 3 2 1 hla_a_02_07 0 0 0.08 hla_a_03_01 0.137 0.071 0.009 1 1 hla_a_11_01 0.06 0.01 0.224 2 2 1 hla_a_23_01 0.023 0.116 0.002 1 2 1 1 2 hla_a_24_02 0.093 0.02 0.231 1 1 1 1 hla_a_30_01 0.016 0.065 0.014 1 1 hla_a_30_02 0.005 0.066 0 2 3 2 3 4 5 hla_a_33_03 0.004 0.041 0.072 2 1 hla_a_68_02 0.007 0.064 0 1 2 1 1 1 hla_a_74_01 0 0.051 0.001 1 hla_b_07_02 0.118 0.062 0.015 2 hla_b_08_01 0.098 0.039 0.002 hla_b_15_01 0.058 0.008 0.121 3 2 2 1 3 1 2 hla_b_15_02 0 0 0.066 3 2 2 1 3 3 3 hla_b_15_03 0.001 0.065 0.001 8 7 7 2 6 8 8 hla_b_18_01 0.061 0.035 0.004 2 1 1 1 hla_b_35_01 0.056 0.061 0.024 3 1 2 1 3 3 hla_b_40_01 0.04 0.01 0.12 2 1 2 1 1 1 hla_b_40_02 0.016 0.003 0.076 2 3 3 1 1 1 hla_b_42_01 0 0.057 0 hla_b_44_02 0.071 0 014 0.002 hla_b_45_01 0.004 0.053 0 2 1 1 1 hla_b_46_01 0 0 0.082 3 1 1 1 1 hla_b_51_01 0.051 0.021 0.04 1 1 hla_b_53_01 0.003 0.11 0 2 2 MAP2K1:p.Q56P MAP2K1:p.V154I MAP2K1:p.V60E MAP2K2:p.C125S MAP2K2:p.L46F MAP2K2:p.N126D MAP2K2:p.V35M NRAS:p.Q61R RES 500 Caucasian Black Asian 80 80 80 80 80 80 80 80 hla_a_01_01 0.143 0.047 0.012 1 hla_a_02_01 0.283 0.114 0.097 1 1 1 1 hla_a_02_03 0 0 0.052 1 1 1 1 hla_a_02_07 0 0 0.08 hla_a_03_01 0.137 0.071 0.009 1 1 hla_a_11_01 0.06 0.01 0.224 1 hla_a_23_01 0.023 0.116 0.002 hla_a_24_02 0.093 0.02 0.231 hla_a_30_01 0.016 0.065 0.014 2 1 1 hla_a_30_02 0.005 0.066 0 3 4 1 hla_a_33_03 0.004 0.041 0.072 1 hla_a_68_02 0.007 0.064 0 1 hla_a_74_01 0 0.051 0.001 hla_b_07_02 0.118 0.062 0.015 1 hla_b_08_01 0.098 0.039 0.002 1 hla_b_15_01 0.058 0.008 0.121 2 1 1 hla_b_15_02 0 0 0.066 2 2 hla_b_15_03 0.001 0.065 0.001 1 7 2 5 1 3 hla_b_18_01 0.061 0.035 0.004 1 hla_b_35_01 0.056 0.061 0.024 2 2 hla_b_40_01 0.04 0.01 0.12 2 1 1 hla_b_40_02 0.016 0.003 0.076 3 1 1 hla_b_42_01 0 0.057 0 hla_b_44_02 0.071 0.014 0.002 hla_b_45_01 0.004 0.053 0 2 1 hla_b_46_01 0 0 0.082 1 hla_b_51_01 0.051 0.021 0.04 hla_b_53_01 0.003 0.11 0 NRAS:p.T58I PIK3CA:p.E545K PLCG2:p.R665W ROS1:p.G2032A RES 500 Caucasian Black Asian 80 80 80 80 hla_a_01_01 0.143 0.047 0.012 1 1 hla_a_02_01 0.283 0.114 0.097 1 2 3 hla_a_02_03 0 0 0.052 1 3 3 hla_a_02_07 0 0 0.08 hla_a_03_01 0.137 0.071 0.009 hla_a_11_01 0.06 0.01 0.224 2 hla_a_23_01 0.023 0.116 0.002 hla_a_24_02 0.093 0.02 0.231 hla_a_30_01 0.016 0.065 0.014 1 hla_a_30_02 0.005 0.066 0 1 1 2 hla_a_33_03 0.004 0.041 0.072 1 hla_a_68_02 0.007 0.064 0 1 2 hla_a_74_01 0 0.051 0.001 hla_b_07_02 0.118 0.062 0.015 hla_b_08_01 0.098 0.039 0.002 hla_b_15_01 0.058 0.008 0.121 1 2 hla_b_15_02 0 0 0.066 1 2 hla_b_15_03 0.001 0.065 0.001 3 2 4 5 hla_b_18_01 0.061 0.035 0.004 1 2 hla_b_35_01 0.056 0.061 0.024 1 1 hla_b_40_01 0.04 0.01 0.12 3 hla_b_40_02 0.016 0.003 0.076 1 3 hla_b_42_01 0 0.057 0 hla_b_44_02 0.071 0.014 0.002 1 2 2 hla_b_45_01 0.004 0.053 0 hla_b_46_01 0 0 0.082 1 hla_b_51_01 0.051 0.021 0.04 1 hla_b_53_01 0.003 0.11 0 1

In all of the above examples, predictions are only shown for a subset of HLA alleles. These are often but not exclusively the most abundant alleles in each ethnic population. Additional alleles are readily predicted.

Moreover, for a given immunization designed to attack resistant variants for a given resistance mutation, multiple peptides, each targeting a separate possible resistance variant that may arise, are utilized to benefit the broadest set of patients.

Example 4

Cancer Subtype Specific Immunogenic Compositions.

Table 7 shows a data summary for the number of mutations found within a population of samples specific to a cancer subtype. Each mutation found within the data set for each disease leads to at least one predicted binder to any one of 33 HLA alleles selected based on being found in at least 5% of any one of the three ethnic populations (Caucasian, Black, Asian). A combination of neoantigenic peptides derived from polypeptides resulting from these mutations can be used in an immunogenic composition. Based on the number of peptides from the mutations selected, a larger percentage of patients may receive a benefit from the vaccine. Table 7 shows the number of mutations that are recurrent in each cancer specific data set. Also shown are the percentage of subjects in each data set that will have at least a single mutation when selecting recurrent mutations. For example, an immunogenic composition for SKCM that includes neoantigenic peptides derived from 64 recurrent mutations described herein covers 90.91% of patients in this population, whereby each subject will contain at least one of the neoantigenic mutations.

recurrence # samples (muts that # that have occur in >= unique at least one Exemplary given # muts in mutation total # disease samples) the set in the set samples percentage SKCM 5 64 230 253 90.91 SKCM 4 200 241 253 95.26 SKCM 3 707 247 253 97.63 SKCM 2 4437 250 253 98.81 SKCM 1 103732 253 253 100 ACC 5 161 90 90 100 ACC 4 219 90 90 100 ACC 3 299 90 90 100 ACC 2 546 90 90 100 ACC 1 10310 90 90 100 BLCA 5 6 35 130 26.92 BLCA 4 9 47 130 36.15 BLCA 3 26 77 130 59.23 BLCA 2 181 121 130 93.08 BLCA 1 25605 130 130 100 BRCA 5 18 320 888 36.04 BRCA 4 25 337 888 37.95 BRCA 3 35 357 888 40.2 BRCA 2 148 475 888 53.49 BRCA 1 31457 886 888 99.77 CESC 5 4 46 194 23.71 CESC 4 7 55 194 28.35 CESC 3 12 65 194 33.51 CESC 2 145 133 194 68.56 CESC 1 25585 194 194 100 CRC 5 15 132 233 56.65 CRC 4 22 142 233 60.94 CRC 3 53 160 233 68.67 CRC 2 711 209 233 89.7 CRC 1 55287 233 233 100 DLBCL 5 0 0 58 0 DLBCL 4 2 8 58 13.79 DLBCL 3 4 13 58 22.41 DLBCL 2 30 38 58 65.52 DLBCL 1 7435 57 58 98.28 HNSC 5 10 83 384 21.61 HNSC 4 15 97 384 25.26 HNSC 3 27 123 384 32.03 HNSC 2 154 227 384 59.11 HNSC 1 43143 384 384 100 KICH 5 0 0 66 0 KICH 4 0 0 66 0 KICH 3 0 0 66 0 KICH 2 24 33 66 50 KICH 1 2576 66 66 100 KIRP 5 9 68 161 42.24 KIRP 4 18 86 161 53.42 KIRP 3 35 104 161 64.6 KIRP 2 117 139 161 86.34 KIRP 1 10482 161 161 100 LIHC 5 2 13 198 6.57 LIHC 4 5 25 198 12.63 LIHC 3 10 38 198 19.19 LIHC 2 33 73 198 36.87 LIHC 1 18574 198 198 100 LUAD 5 11 134 401 33.42 LUAD 4 17 152 401 37.91 LUAD 3 35 185 401 46.13 LUAD 2 611 330 401 82.29 LUAD 1 101222 399 401 99.5 MM 5 6 49 205 23.9 MM 4 8 55 205 26.83 MM 3 16 71 205 34.63 MM 2 51 101 205 49.27 MM 1 7116 204 205 99.51 PRAD 5 24 104 261 39.85 PRAD 4 38 133 261 50.96 PRAD 3 83 174 261 66.67 PRAD 2 205 213 261 81.61 PRAD 1 10174 261 261 100 STAD 5 150 141 289 48.79 STAD 4 245 156 289 53.98 STAD 3 613 201 289 69.55 STAD 2 2729 269 289 93.08 STAD 1 97578 289 289 100 TGCT 5 14 80 155 51.61 TGCT 4 25 99 155 63.87 TGCT 3 64 124 155 80 TGCT 2 338 149 155 96.13 TGCT 1 7632 155 155 100 THCA 5 5 283 405 69.88 THCA 4 5 283 405 69.88 THCA 3 7 287 405 70.86 THCA 2 31 300 405 74.07 THCA 1 4439 405 405 100 UCS 5 2 9 56 16.07 UCS 4 10 31 56 55.36 UCS 3 19 41 56 73.21 UCS 2 55 53 56 94.64 UCS 1 3805 56 56 100 CLL 5 6 46 263 17.49 CLL 4 19 74 263 28.14 CLL 3 38 100 263 38.02 CLL 2 157 167 263 63.5 CLL 1 7870 263 263 100 GBM 5 14 100 291 34.36 GBM 4 24 125 291 42.96 GBM 3 45 153 291 52.58 GBM 2 221 252 291 86.6 GBM 1 14142 291 291 100 KIRC 5 4 25 417 6 KIRC 4 8 41 417 9.83 KIRC 3 23 78 417 18.71 KIRC 2 291 292 417 70.02 KIRC 1 17725 417 417 100 LAML 5 11 93 196 47.45 LAML 4 12 95 196 48.47 LAML 3 16 101 196 51.53 LAML 2 27 114 196 58.16 LAML 1 1458 195 196 99.49 LUSC 5 2 14 178 7.87 LUSC 4 4 22 178 12.36 LUSC 3 15 50 178 28.09 LUSC 2 130 138 178 77.53 LUSC 1 42062 178 178 100 OV 5 10 72 316 22.78 OV 4 12 80 316 25.32 OV 3 14 86 316 27.22 OV 2 56 151 316 47.78 OV 1 12840 316 316 100 PAAD 5 53 146 146 100 PAAD 4 69 146 146 100 PAAD 3 123 146 146 100 PAAD 2 398 146 146 100 PAAD 1 23715 146 146 100 UCEC 5 30 168 248 67.74 UCEC 4 81 196 248 79.03 UCEC 3 302 217 248 87.5 UCEC 2 2797 237 248 95.56 UCEC 1 112636 248 248 100 COAD 5 3 19 70 27.14% COAD 4 7 20 70 28.57% COAD 3 11 25 70 35.71% COAD 2 84 44 70 62.86% COAD 1 16670 70 70 100.00% READ 5 0 0 39 0.00% READ 4 2 8 39 20.51% READ 3 5 16 39 41.03% READ 2 33 29 39 74.36% READ 1 12132 39 39 100.00%

Table 8 shows the specific recurrent mutations for each cancer subtype, as well as the peptides that each mutation generates and the flanking peptide that includes the peptides (“ACC”, “BLCA”, “BRCA”, “CESC”, “COAD”, “CLL”, “CRC”, “DLBCL”, “GBM”, “HNSC”, “KICH”, “KIRC”, “KIRP”, “LAML”, “LIHC”, “LUAD”, “LUSC”, “MM”, “OV”, “PAAD”, “PRAD”, “READ”, “SKCM”, “STAD”, “TGCT”, “THCA”, “UCEC”, and “UCS”). Frameshift mutations are denoted with a “fs”. “Del” and “Ins” indicate deletions and inserts. The number of peptides that are generated from each mutation that binds to a specific HLA allele are shown. The recurrent mutations include frameshift mutations and create HLA binders across many alleles.

TABLE 8 Mutation_Context_Sequence Peptides (SEQ ID NOS 3799-33502, (SEQ ID NOS 81-3798, respectively, respectively, in Exemplary gene cDNA Change Protein Change in order of appearance) order of appearance) Diseases A2M c.2195G>A p.R732Q FYESDVMGRGHARLVHVEEPHTETV[p. VQKYFPETW,QKYFPETWI,ETVQKYFPET,VQKYFPETWI,Q CRC R732Q]QKYFPETWIWDLVVVNSAGVAE KYFPETWIW,EPHTETVQKY VGVT A2ML1 c.1960_1961 p.S654fs YDQCPVSGPWDFPQPLIDPMPQGHS HSEPAFHYL,MPQGHSEPA,PQGHSEPAF,GHSEPAFHY,FH LUAD insC [p.S654fs]EPAFHYLEALVL* YLEALVL,EPAFHYLEA,QGHSEPAFHY,EPAFHYLEAL,MPQ GHSEPAF,SEPAFHYLEA AADA c.796G>A p.A266 VPLLSRKFMVTSLCNYLAIDLSWRD[p. IDLSWRDTI,SWRDTILNG,DTILNGTCV,IDLSWRDTIL CRC CL4 T A266T]TILNGTCVPPDVWRKYEKWLSPDNIP AASS c.2634_2635 p.T878 KTIDLVAYGDINGFSAMAKTVGLPT[p. MAKTVGLPTR,LPTRHGSQNV GBM insC fs T878fs]RHGSQNVA* ABCA c.1154G>T p.R385I TGEKPYTCGECGKTFRQSANLYVHR[p. VHRIIHTGEK,QSANLYVHRI UCEC 11P R385I]IIHTGEKP YKCEDCGKAFGRYTALNQ ABCA3 c.285G>C p.E95D TFPPPGDTWELAYIPSHSDAAKTVT[p.E KTVTDTVRR,VTDTVRRALV,AAKTVTDTVR,DAAKTVT KIRC 95D]DTVRRALVINMRVRGFPSEKDFEDYI DTV,TVTDTVRRAL ABCA5 c.4427G>A p.R1476 PQITLLDEPSTGMDPKAKQHMWRAI[p. HMWRAIQTA,IQTAFKNRK,MWRAIQTAF,AIQTAFKNR,Q UCEC Q R1476Q]QTAFKNRKRAAILTTHYME TAFKNRKR,MWRAIQTAFK,AIQTAFKNRK,HMWRAIQTAF, EAEAVCD KQHMWRAIQ,RAIQTQFKNR,QHMWRAIQTA ABCA6 c.917de|T p.L306 FVTIIITFTQIIVMTGFMVIFILFF[p.L3 MVIFILFFY,VIFILFFYM,ILFFYMAYL,LFFYMAYLW,FILF STAD fs 06fs]YMAYLW* FYMAY,MVIFILFFYM,VIFILFFYMA,FILFFYMAYL,ILFFY MAYLW,FMVIFILFFY,IFILFFYMAY ABCA8 c.2086G>A p.A696T STQFMDEADILADRKVFLSQGKLKC[p. KLKCTGSSL,CTGSSLFLK,TGSSLFLKK,LKCTGSSLF,FLSQGKL CRC A696T]TGSSLFLKKKWGIGYHLSLQLN KCT,CTGSSLFLKK,KCTGSSLFLK,KLKCTGSSLF,GKLKCTG EICV SSL,LKCTGSSLFL ABCA8 c.2525G>A p.R842Q RLVEMEQVLSSLNKMRKTIGGVALW[p. ALWQQQICA,WQQQICAIA,ALWQQQICAI CRC R842Q]QQQICAIARVRLLKLKHERKAL LALL ABCA8 c.3472G>A p.E1158K NSGIWSFCFYVVTVFSVAGFAFSIF[p.E AGFQFSIFK,IFKSDIPFI,SIFKSDIPF,FKSDIPFIF,SIFKSDIPF CRC 1158K]KSDIPFIFTFLIPPATMIGCLFLSSH I,VAGFAFSIFK,IFKSDIPFIF,KSDIPFIFTF,FAFSIFKSDI, FSIFKSDIPF ABCB1 c.1400G>T p.R467L RLYDPTEGMVSVDGQDIRTINVRFL[p. RTINVRFLL,FLLEIIGVV,RFLLEIIGV,INVRFLLEI,FLLEIIGVVS, LUAD R467L]LEIIGVVSQEPVLFATTIAENIRYGR TINVRFLLEI,RFLLEIIGVV,RTINVRFLLE ABCB1 c.1581_1582 p.R527fs VKEANAYDFIMKLPHKFDTLVGERG[p. TLVGERGPV,GERGPVEWW,AEAEDRHCT,DTLVGERGPV, STAD de|AG R527fs]PVEWWAEAEDRHCTCPGSQP GERGPVEWWA QDPPAG* ABCB6 c.953de|G p.G318fs LTEKAPWNSLAWTVTSYVFLKFLQG[p. FLQGVALAV,FLKFLQGVA,LKFLQGVAL,YVFLKFLQGV,FLK STAD G318fs]VALAVQAS* FLQGVAL,KFLQGVALAV,LKFLQGVALA ABCB8 c.1034G>A p.R345H SRQCQEQIARAMGVADEALGNVRTV[p. NVRTVHAFA,GNVRTVHAF,VRTVHAFAM,ALGNVRTVHA, CRC R345H]HAFAMEQREEERY TVHAFAMEQR,NVRTVHAFAM,LGNVRTVHAF GAELEACRCRAEE ABCC10 c.1708C>T p.R570W RMLILPLNNFPVVVINGLLEAKVSLD[p. SLDWIQLFL,VSLDWIQLF,DWIQLFLDL,LEAKVSLDW,KVSL GBM R570]WIQLFLDLPNHNPQ DWIQLF,AKVSLDWIQL,LEAKVSLDWI,LDWIQLFLDL AYYSPDPPAEPS ABCC4 c.2648de|T p.L883 VAVIPWIAIPLVPLGIIFIFLRRYF[p. IFLRRYFWK,FIFLRRYFW,RYFWKRQEM,FLRRYFWKR,FIFL STAD fs L883fs]WKRQEM* RRYFWK,IFIFLRRYFW,IFLRRYFWKR,RRYFWKRQEM ABCC5 c.3269de|T p.L1090 HAYNKGQEFLHRYQELLDDNQAPFF[p. WLCGWTSSA,SASPSSPPR,RVRCGGWLC,NQAPFFCLR,QA KIRC fs L1090fs]CLRVRC PFFCLRV,NQAPFFCLRV,SSASPSSPPR,RVRCGGWLCG,DN GGWLCGWTSSASPSSPPRG* QAPFFCLR,CLRVRCGGWL ABCC8 c.1535A>G p.Y512 STLEYSNERLKQTNEMLRGIKLLKL[p. IKLLKLCAW,LKLCAWENI,KLCAWENIF,LLKLCAWENI,KLC TGCT C Y512C]CAWENIFRTRVETTRRKEMTS AWENIFR,CAWENIFRTR,LKLCAWENIF LRAFA ABCC9 c.1397T>C p.L466P IIMGVILLYNLLGSSALVGAAVIVL[p. AVIVLPAPI,IVLPAPIQY,VLPAPIQYF,LPAPIQYFI,VLPAPIQY TGCT L466P]PAPIQYFIATKLAEAQKSTLDYSTER FI,IVLPAPIQYF,AAVIVLPAPI,VIVLPAPIQY,LPAPIQYFIA ABCD1 c.1816T>C p.S606P DVVHLHHILQREGGWEAMCDWKDVL[p.S606P] LPGGEKQRI,DVLPGGEKQR CESC PGGEKQRIGMARMFYHRPKYALLDEC ABCD1 c.507C>A p.H169Q ATFVNSAIRYLEGQLALSFRSRLVA[p.H169Q]QAY RLVAQAYRL,VAQAYRLYF,RSRLVAQAY,LVAQAYRLY,RLV TGCT RLYFSQQTYYRVSNMDGRLRNPD AQAYRLY,RSRLVAQAYR,LVAQAYRLYF,SFRSRLVAQA,FRSRL VAQAY,SRLVAQAYRL ABI1 c.1335G>T p.K445N DYEDEEAAVVQYNDPYADGDPAWAP[p.K445N]NNY DPAWAPNNY,AWAPNNYIEK,WAPNNYIEKV,DPAWAPNNYI UCEC IEKVVAIYDYTKDKDDELSFMEG ABL2 c.55C>A p.P19T MGQQVGRVGEAPGLQQPQ[p.P19T]TRGIRGSSAARP LQQPQTRGI,QTRGIRGSSA TGCT SGRRRDPAGRTTET ABTB1 c.747_748 p.L249fs TIEPPPADPRLREDMALLADCALPP[p.L249fs]RAPR* CALPPRAPR,LLADCALPPR,DCALPPRAPR LAML insC ACACA c.5191C>T p.R1731C ARAEGIPRIYVSANSGARIGLAEEI[p.Rl731C]CHMFH GLAEEICHM,EICHMFHVA,LAEEICHMF,ICHMFHVAW,EEI CRC VAVVVDPEDPYKGYRYLYLTPQ CHMFHV,GLAEEICHMF,IGLAEEICHM,EEICHMFHVA,AEE ICHMFHV ACACB c.6952G>C p.E2318Q VAVQFADFHDTPGRMLEKGVISDIL[p.E2318Q]QWK ILQWKTART,VISDILQWK,QWKTARTFL,DILQWKTAR,LQ BLCA TARTFLYWRLRRLLLEDQVKQEI WKTARTF,GVISDILQWK,ILQWKTARTF,QWKTARTFLY,LQ WKTARTFL ACACB c.763de|G p.G255fs EHKKLDLHRDFTVASPAEFVTRFGG[p.G255fs]IGSS SSRRCLLPT,RFGGIGSSR,RCLLPTTGL,SSRRCLLPTT,AEFVTR STAD RRCLLPTTGLPP* FGGI,RRCLLPTTGL ACADM c.143T>G p.F48C QHTKANRQREPGLGFSFEFTEQQKE[p.F48C]CQAT QQKECQATA,QQKECQATAR,CQATARKFAR, CRC ARKFAREEIIPVAAEYDKTGEY KECQATARKF,TEQQKECQAT ACADS c.989G>A p.R330H TKLQVIQFKLADMALALESARLLTW[p.R330H]HA RLLTWHAAM,LLTWHAAML,LTWHAAMLK,HAAMLKDNK, KIRC,PRAD AMLKDNKKPFIKEAAMAKLAASEA SARLLTWHA,ARLLTWHAA,RLLTWHAAML,LLTWHAAMLK, SARLLTWHAA,HAAMLKDNKK,ESARLLTWHA,LESARLL TWH,ARLLTWHAAM ACBD3 c.671G>T p.R224L REEEERERLQKEEEKRRREEEERLR[p.R224L]LEE REEEERLRL LUAD EERRRIEEERLRLEQQKQQIMAA ACOT9 c.149G>A p.R50Q GPQNPKKQGIFHIHEACSSIHVNHV[p.R50Q]QDKLR VQDKLREIV,SIHVNHVQDK,HVNHVQDKLR CRC EIVGASTNWRDHVKAMEERKL ACP1 c.368de|A p.Q123fs DLNRKSNQVKTCKAKIELLGSYDPQ[p.Q123fs]NNLL SLTRPHPEV,LLKIPIMGM,TLRRCTSSV,IMGMTLTLR,MGM STAD LKIPIMGMTLTLRRCTSSVSGAAERSWRRPTEAGSCP TLTLRR,SSVSGAAER,RSWRRPTEA,LTRPHPEVL,GAAERS AAASLTRPHPEVLHFSVGV* WRR,CTSSVSGAA,EVLHFSVGV,RPHPEVLHF,HPEVLHFSV, NLLLKIPIM,GSYDPQNNL,TEAGSCPAA,GSCPAAASL,AAAS LTRPH,AERSWRRPT,LLLKIPIMGM,LTLRRCTSSV,SLTRPHP EVL,IMGMTLTLRR,SYDPQNNLLL,ASLTRPHPEV,LTRPHPE VLH,PIMGMTLTLR,SGAAERSWRR,IPIMGMTLTL,RPTEAG SCPA,GSYDPQNNLL,LKIPIMGMTL,TEAGSCPAAA,PEVLH FSVGV,DPQNNLLLKI ACP6 c.86T>G p.V29G GVFSMRLWTPVGVLTSLAYCLHQRR[p.V29G]GA CLHQRRGAL,HQRRGALAE,QRRGALAEL,CLHQRRGALA,H KIRP LAELQEADGQCPVDRSLLKLKMVQ QRRGALAEL,YCLHQRRGAL ACPP c.127C>T p.R43W FLFLLFFWLDRSVLAKELKFVTLVF[p.R43W]WH TLVFWHGDR,LKFVTLVFW,FWHGDRSPI,VTLVFWHGDR, BRCA GDRSPIDTFPTDPIKESSWPQGFG VFWHGDRSPI ACPP c.314G>A p.R105Q ELGEYIRKRYRKFLNESYKHEQVYI[p.Rl05Q]QST HEQVYIQST,IQSTDVDRTL CRC DVDRTLMSAMTNLAALFPPEGVS ACPP c.961G>A p.E321K LQMALDVYNGLLPPYASCHLTELYF[p.E321K]KK HLTELYFKK,LYFKKGEYF,ELYFKKGEY,KKGEYFVEM,LYFKK BLCA GEYFVEMYYRNETQHEPYPLMLPG GEYFV,SCHLTELYFK,ELYFKKGEYF,TELYFKKGEY,FKKGEYF VEM,KKGEYFVEMY ACR c.837G>T p.W279C YVVVGITSWGVGCARAKRPGIYTAT[p.W279C]C GIYTATCPY,IYTATCPYL,CPYLNWIAS,TATCPYLNW,GIYTA KICH PYLNWIASKIGSNALRMIQSATPPP TCPYL,YTATCPYLNW,TATCPYLNWI ACSBG2 c.750T>G p.I250M AVLIYTSGTTGIPKGVMLSHDNITW[p.I250M]MA NITWMAGAV,TWMAGAVTK,MAGAVTKDF,LSHDNITWM,MLSH KIRP GAVTKDFKLTDKHETWSYLPLSH DNITWM,ITWMAGAVTK,MAGAVTKDFK,DNIT WMAGAV,WMAGAVTKDF ACSL3 c.562A>T p.T188S AIFCETRAEWMIAAQACFMYNFQLV[p.T188S]SLY FMYNFQLVS,FQLVSLYAT,QLVSLYATL,MYNFQLVSL,YNF CLL ATLGGPAIVHALNETEVTNIITS QLVSLY,FMYNFQLVSL,FQLVSLYATL,SLYATLGGPA,MYNF QLVSLY,YNFQLVSLYA ACSM2A c.1206_1207 p.L402fs PGYMGTAASCYDVQIIDDKGNVLPP[p.L402fs]RHRRR HQAYRHLLW,AYRHLLWLC,SSQHSRRLL,SQHSRRLLA,HSR KIRC insC HWHQGQTHQAYRHLLWLCGQSRQDSSQHSRRLLAPW RLLAPW,RLLAPWRPG,HQGQTHQAY,NVLPPRHRR,VLPP RPGNQR* RHRRR,QGQTHQAYR,RHWHQGQTH,QAYRHLLWL,HQA YRHLLWL,THQAYRHLLW,QTHQAYRHLL,SSQHSRRLLA,H SRRLLAPWR,WHQGQTHQAY,NVLPPRHRRR,HQGQTHQ AYR,HLLWLCGQSR,LAPWRPGNQR,GQTHQAYRHL,GQSR QDSSQH,SQHSRRLLAP,QHSRRLLAPW ACSM2B c.585G>T p.K195N VASECPSLRIKLLVSEKSCDGWLNF[p.K195N]NK GWLNFNKLL UCEC LLNEASTTHHCVETGSQEASAIYF ACTA1 c.823G>T p.G275C ITIGNERFRCPETLFQPSFIGMESA[p.G275C]CI FIGMESACI,SACIHETTY,ESACIHETT,MESACIHET,ESACIH LUAD HETTYNSIMKCDIDIRKDLYANNV ETTY,CIHETTYNSI,SFIGMESACI,MESACIHETT ACTG1 c.64G>C p.A22P MEEEIAALVIDNGSGMCKAGF[p.A22P]PGDDAP FPGDDAPRA,FPGDDAPRAV MM RAVFPSIVGRPRHQGVMVGM ACTL6A c.264de|A p.L88fs GPTYYIDTNALRVPRENMEAISPLK[p.L88fs]MGW KMGWLKTGI,GIVSKLFWI,WLKTGIVSK,KLFWIIPTK,ILFSC STAD LKTGIVSKLFWIIPTKCMSNQKPVSILFSCQRHRG QRHR,VSILFSCQR,IVSKLFWII,NQKPVSILF,PTKCMSNQK, ILEQRERN* MEAISPLKM,LKTGIVSKL,SKLFWIIPT,MSNQKPVSI,KMG WLKTGIV,WLKTGIVSKL,GIVSKLFWII,KLFWIIPTKC,AISPLK MGWL,CMSNQKPVSI,ISPLKMGWLK,GWLKTGIVSK,SILFS CQRHR,NMEAISPLKM,LKMGWLKTGI,LKTGIVSKLF,MSN QKPVSIL,SNQKPVSILF,FSCQRHRGIL,EAISPLKMGW ACTL7B c.1061G>A p.R354H TGFKEEMAANVLLCGGCTMLDGFPE[p.R354H]HFQR HFQRELSLL,DGFPEHFQR,FPEHFQREL,TMLDGFPEH,MLD CRC ELSLLCPGDSPAVAAAPERKTS GFPEHF,EHFQRELSL,MLDGFPEHF ACTL7B c.631G>A p.E211K IYSYGKTSGLVVESGHGVSHWPIS[p.E211K]KG VSHVVPISK,VPISKGDVL,GVSHVVPISK,HVVPISKGDV CESC DVLPGLTSRADYAGGDLTNYLMQL ACTL9 c.992G>A p.R331H EVPGLSPVGLSTMAKQSLRKLSLEM[p.R331H]HAD LEMHADLAQ,HADLAQNVL,KLSLEMHADL,EMHADLAQN CRC LAQNVLLCGGSSLFTGFEGRFRA V,MHADLAQNVL ACTN2 c.2677G>T p.D893Y AYSGPGSVPGALDYAAFSSALYGES[p.D893Y]YL* SSALYGESY,SALYGESYL,FSSALYGESY,SSALYGESYL LUAD ACVR1 c.617G>A p.R206H ADLLDHSCTSGSGSGLPFLVQRTVA[p.R206H]HQI HQITLLECV,TVAHQITLL,RTVAHQITL,FLVQRTVAH,VQRT UCEC TLLECVGKGRYGEVWRGSWQGEN VAHQI,RTVAHQITLL,VQRTVAHQIT,QRTVAHQITL,HQITLLECVG ACVR1 c.869C>T p.S290L FIASDMTSRHSSTQLWLITHYHEMG[p.S290L]LL GLLYDYLQL,LLYDYLQLT,ITHYHEMGL,HYHEMGLLY,HEM CRC YDYLQLTTLDTVSCLRIVLSIASG GLLYDY,GLLYDYLQLT,LLYDYLQLTT,ITHYHEMGLL,THYHE MGLLY,YHEMGLLYDY,HEMGLLYDYL,MGLLYDYLQL ADAD1 c.32C>T p.SIIL MASNNHWFQS[p.SllL]LQVPSFAQMLKKNLPVQPA SNNHWFQSL,FQSLQVPSF,LQVPSFAQM,FQSLQVPSFA,S UCEC TKTITTP LQVPSFAQM,LQVPSFAQML,WFQSLQVPSF,ASNNHWFQSL ADAD2 c.131G>A p.G44E LAASLQISPQPRPWRPLPAQAQSAW[p.G44E]EPAP QSAWEPAPA,EPAPAPATY,AQAQSAWEP,AQSAWEPAP, ACC APATYRAEGGWPQVSVLRDSGP WEPAPAPAT,AQSAWEPAPA,AQAQSAWEPA,SAWEPAP APA,WEPAPAPATY ADAM23 c.1139A>T p.K380M EKDQIDITTNPVQMLHEFSKYRQRI[p.K380M]MQ RIMQHADAV,MQHADAVHL,KYRQRIMQH,FSKYRQRIM,I KIRC HADAVHLISRVTFHYKRSSLSYFG MQHADAVH,IMQHADAVHL,MQHADAVHLI,KYRQRIMQ HA,RQRIMQHADA,SKYRQRIMQH,RIMQHADAVH ADAM28 c.217_218 p.K73fs QEQFETELKYKMTINGKIAVLYLKK[p.K73fs]KQEP CTRLHGNIL,KQEPPCTRL,KIAVLYLKKK,YLKKKQEPPC,KKQ STAD insA PCTRLHGNIL* EPPCTRL,KQEPPCTRLH ADAM29 c.613G>A p.V205I IDNSTQKQSSYVGWWIHFRIVEIVV[p.V205I]II RIVEIVVII,VIIDNYLYI,VVIIDNYLY,IVVIIDNYL,FRIVEIVVI, GBM DNYLYIRYERNDSKLLEDLYVIVN IIDNYLYIRY,VVIIDNYLYI,VIIDNYLYIR,HFRIVEIVVI,IVV IIDNYLY,EIVVIIDNYL,VEIVVIIDNY ADAM30 c.2223G>T p.Q741H LKPKQEKMPLSKAKTEQEESKTKTV[p.Q741H]H KTKTVHEES,KTKTVHEESK,KTVHEESKTK LUAD EESKTKTGQEESEAKTGQEESKAKT ADAM30 c.289_290 p.G97L KHVLHLWPKRLLLPRHLRVFSFTEH[p.G97L]LEL RVFSFTEHL,SFTEHLELL,FSFTEHLEL,LELLEDHPY,HLELLED SKCM GG>TT LEDHPYIPKDCNYMGSVKESLDSK HPY,VFSFTEHLEL,LRVFSFTEHL,FSFTEHLELL,LELLEDHPYI ADAM30 c.941C>A p.S314Y SSDWAHLYLQRKYNDALAWSFGKVC[p.S314Y]YLE WSFGKVCYL,CYLEYAGSV,AWSFGKVCY,FGKVCYLEY,SFG CRC YAGSVSTLLDTNILAPATWSAHE KVCYLEY,LAWSFGKVCY ADAM32 c.1676G>A p.R559Q DRNNKYVFCGWRNLICGRLVCTYPT[p.R559Q]QK LVCTYPTQK,CTYPTQKPF,RLVCTYPTQK,CTYPTQKPFH,VC CRC PFHQENGDVIYAFVRDSVCITVDY TYPTQKPF ADAM9 c.767G>A p.R256Q NQTAVREEMILLANYLDSMYIMLNI[p.R256Q]QIV YIMLNIQIV,IMLNIQIVL,MLNIQIVLV,MYIMLNIQI,SMYIM UCEC LVGLEIWTNGNLINIVGGAGDVL LNIQI,YIMLNIQIVL,IMLNIQIVLV,MYIMLNIQIV,IQIVLVGLEI ADAMTS12 c.1075G>A p.E359K LNPVHHDVAVLLTRKDICAGFNRPC[p.E359K]KT CAGFNRPCK,CKTLGLSHL,KTLGLSHLSG,FNRPCKTLGL, UCS LGLSHLSGMCQPHRSCNINEDSGL AGFNRPCKTL ADAMTS12 c.3157C>G p.P1053A RPRMLTTPTGPESMSTSTPAISSPS[p.P1053A]AT TPAISSPSA,ISSPSATTA,AISSPSATTA,SSPSATTASK,STPAIS CESC TASKEGDLGGKQWQDSSTQPELSS SPSA,TPAISSPSAT ADAMTS14 c.712G>T p.G238C QQEWAEPDGDLHNEAFGLGDLPNLL[p.G238C]CLV DLPNLLCLV,NLLCLVGDQL LUAD GDQLGDTERKRRHAKPGSYSIEV ADAMTS16 c.2449G>A p.D817N LRRYYLNGHWTVDWPGRYKFSGTTF[p.D817N]NY FSGTTFNYR,KFSGTTFNY,TTFNYRRSY,SGTTFNYRR,FSGTT CRC RRSYNEPENLIATGPTNETLIVEL FNYRR,KFSGTTFNYR,YKFSGTTFNY,GTTFNYRRSY ADAMTS17 c.1715A>C p.N572T SPWGAWSMCSRTCGTGARFRQRKCD[p.N572T]TP RQRKCDTPP,RQRKCDTPPP TGCT PPGPGGTHCPGASVEHAVCENLPC ADAMTS2 c.2842G>A p.D948N WEPCSQTCGRTGMQVRSVRCIQPLH[p.D948N]NN LHNNTTRSV,SVRCIQPLHN,LHNNTTRSVH CLL TTRSVHAKHCNDARPESRRACSRE ADAMTS20 c.1622G>T p.R541L KLHKGCFTQHVPPADGTDCGPGMHC[p.R541L]LH CLHGLCVNK,GMHCLHGLCV,GPGMHCLHGL LUAD GLCVNKETETRPVNGEWGPWEPYS ADAMTS20 c.3751C>A p.R1251S GKTTRQVLCMNYHQPIDENYCDPEV[p.R1251S]SP SPLMEQECSL LUAD LMEQECSLAACPPAHSHFPSSPVQ ADAMTS4 c.466C>T p.R156W TINGDPESVASLHWDGGALLGVLQY[p.R156W]WG VLQYWGAEL,ALLGVLQYW,QYWGAELHL,LQYWGAELH,L CRC AELHLQPLEGGTPNSAGGPGAHIL LGVLQYWGA,LQYWGAELHL,GALLGVLQYW,WGAELHLQPL ADAMTS5 c.1645C>A p.L549M QGQMVCLTKKLPAVEGTPCGKGRIC[p.L549M]MQ KGRICMQGK,TPCGKGRICM LUAD GKCVDKTKKKYYSTSSHGNWGSWG ADAMTS8 c.1570G>A p.V524M TPCGPGHLCSEGSCLPEEEVERPKP[p.V524M]MA KPMADGGWA,EEVERPKPM,MADGGWAPW,PMADGG GBM DGGWAPWGPWGECSRTCGGGVQFS WAPW,EEEVERPKPM ADAMTS9 c.1975G>T p.G659W FKSCNTEPCLKQKRDFRDEQCAHFD[p.G659W]WK HFDWKHFNI,CAHFDWKHF,WKHFNINGL,DEQCAHFDW, LUAD HFNINGLLPNVRWVPKYSGILMKD AHFDWKHFNI,WKHFNINGLL ADAMTSL4 c.2332_2333 p.G778fs TSCSRSCGPGTQHRQLQCRQEFGGG[p.G778fs]WL WLLGAPGAL,GSWLSLEPV,SLEPVLRAV,RAVRPGPEK,SWLSLEPVL, STAD insG LGAPGALWTSPPAQHHPVLPAAPLWPLGSWLSLEPV HPVLPAAPL,LPAAPLWPL,SPPAQHHPV,PPAQHH LRAVRPGPEKPAGSLCWEQW* PVL,WPLGSWLSL,GPEKPAGSL,RQEFGGGWL,QEFGGGW LL,LLGAPGALW,AQHHPVLPA,QHHPVLPAA,APLWPLGS W,VLPAAPLWPL,AQHHPVLPAA,WLSLEPVLRA,LWPLGS WLSL,AVRPGPEKPA,SWLSLEPVLR,SLEPVLRAVR,TSPPAQHH PV,SPPAQHHPVL,APLWPLGSWL,RQEFGGGWLL,WLL GAPGALW,GSWLSLEPVL,QEFGGGWLLG,HPVLPAAPLW ADCY2 c.260C>T p.A87V LAVFFALGLEVEDHVAFLITVPTAL[p.A87V]VI LVIFFAIFI,VIFFAIFIL,LITVPTALV,TVPTALVIF,TALVIFFAI, DLBCL FFAIFILVCIESVFKKLLRLFSLV PTALVIFFA,ALVIFFAIF,ITVPTALVI,VPTALVIFF,FLITVPTALV, ALVIFFAIFI,VIFFAIFILV,ITVPTALVIF,TVPTALVIFF, TALVIFFAIF,PTALVIFFAI,LVIFFAIFIL,VPTALVIFFA ADCY2 c.2662G>A p.V888I HVAEHFLARSLKNEELYHQSYDCVC[p.V888I]IM SYDCVCIMF,IMFASIPDF,QSYDCVCIM,HQSYDCVCI,IMFA OV FASIPDFKEFYTESDVNKEGLECL SIPDFK,CIMFASIPDF,HQSYDCVCIM,QSYDCVCIMF ADCY2 c.3046C>A p.P1016T SFNDFKLRVGINHGPVIAGVIGAQK[p.1016] AQKTQYDIW,TQYDIWGNTV,GVIGAQKTQY LUAD TQYDIWGNTVNVASRMDSTGVLDKIQ ADCY5 c.1982G>A p.R661H SIETFLILRCTQKRKEEKAMIAKMN[p.R661H] MIAKMNHQR,KAMIAKMNH,KMNHQRTNS,HQRTNSIGH, CRC HQRTNSIGHNPPHWGAERPFYN MNHQRTNSI,KMNHQRTNSI,AMIAKMNHQR HLGG ADD3 c.1708G>A p.E570K HGPPAPPNPFSHLTEGELEEYKRTI[p.E570K]K TIKRKQQGL,RTIKRKQQGL UCEC RKQQGLEDAEQELLSDDASSVSQIQ ADGB c.3371C>T p.S1124L PCNSFAIKEIRDYYIPNDKKILFRY[p.S1124L]L ILFRYLVKV,KILFRYLVK,LFRYLVKVL,KKILFRYLV,KILFRYLVK UCEC VKVLTPQPATIQVRTSKPDAFIKLQ V,ILFRYLVKVL,KKILFRYLVK,LVKVLTPQPA ADH1A c.461A>T p.D154V SRFTCRRKPIHHFLGISTFSQYTVV[p.D154V]V YTVVVENAV,VVVENAVAK,TFSQYTVVV,SQYTVVVEN,STFSQYTV KIRC ENAVAKIDAASPLEKVCLIGCGFST VV,SQYTVVVENA,VVVENAVAKI,TVVVENAVAK,YTVVVENAV A,VENAVAKIDA ADNP2 c.965de|C p.S322fs NSPSPAAGQPVTVAQGAPGSLTHSP[p.S322fs] SLTHSPLLL,GSLTHSPLL,LTHSPLLLA,SLTHSPLLLA,APGSLTHSPL STAD LLLANPT* AFF2 c.1790G>A p.R597H VKTNASQVPAEPKERPLLSLIREKA[p.R597H]HP KAHPRPTQK,LIREKAHPR,REKAHPRPT,KAHPRPTQKI,SLIREKAHPR PRAD RPTQKIPETKALKHKLSTTSETVS AFF3 c.2755G>A p.E919K INKNEKMLRSPISPLSDASKHKYTS[p.E919K]KD ASKHKYTSK,TSKDLTSSSR,SKHKYTSKDL BLCA LTSSSRPNGNSLFTSASSSKKPKA AFP c.545C>G p.A182G TFMNKFIYEIARRHPFLYAPTILLW[p.Al82G]GAR LLWGARYDK,LWGARYDKI,TILLWGARY,PTILLWGAR,PTIL LUAD YDKIIPSCCKAENAVECFQTKAA LWGARY,YAPTILLWGA,LLWGARYDKI,ILLWGARYDK,LYAPTILLWG AGAP1 c.381de|C p.G127fs GGRFKKEIVVDGQSYLLLIRDEGGP[p.G127fs]R LPCGWTLLY,SLPCGWTLL,LLYLSSAWR,YLSSAWRMK,RSL STAD RRSLPCGWTLLYLSSAWRMK* PCGWTL,LYLSSAWRM,WTLLYLSSA,GPRRRSLPC,TLLYLSS AW,LLYLSSAWRM,RSLPCGWTLL,LIRDEGGPRR,LYLSSAW RMK,SLPCGWTLLY,TLLYLSSAWR,RRSLPCGWTL,WTLLYL SSAW,LPCGWTLLYL AGAP3 c.2296C>T p.R766W VWEGALGGYSKPGPDACREEKERWI[p.R766W] WIWAKYEQK,IWAKYEQKL,KERWIWAKY,WAKYEQKLF,E GBM WAKYEQKLFLAPLPSSDVPLGQQLLR EKERWIWA,WIWAKYEQKL,IWAKYEQKLF,RWIWAKYEQK, REEKERWIWA AGAP6 c.207de|C p.D69fs MAAAVQPAEVTVEVGEDLHMHHVRD TLKQKLWSL,HVRDGRCLK,CLKLWSLTF,LWSLTFLPI,YSRG KIRC [p.D69fs]GRCLKLWSLTFLPIQSQAQYS TLKQK,KQKLWSLTL,HMHHVRDGR,LPIQSQAQY,LKLWSL RGTLKQKLWSLTLLPIQRQA TFL,SQAQYSRGT,QKLWSLTLL,KLWSLTFLPI,KLWSLTLLPI, QYSRGTLKQML* CLKLWSLTFL,KQKLWSLTLL,RCLKLWSLTF,HVRDGRCLKL, FLPIQSQAQY,LTFLPIQSQA,DGRCLKLWSL,SQAQYSRGTL, LKQKLWSLTL,YSRGTLKQML AGAP6 c.380G>T p.S127l NPSANPEASTIFQRNSQTDVVEIRR[p.S127I] RRINCTNHV,RINCTNHVSA CLL,PRAD INCTNHVSAVRFSQQYSLCSTIFLDD AGAP7 c.211de|G p.E71fs AAAVQPAEVTVEVGEDLHMHHVRDR[p.E71fs]RCLK HMHHVRDRR,HVRDRRCLK,CLKLWSLTL,RRCLKLWSL,LKL KIRC LWSLTLLPIQRQAQYSRGTLKQML* WSLTLL,KLWSLTLLPI,CLKLWSLTLL,HVRDRRCLKL,DRRCLKLWSL, RCLKLWSLTL,YSRGTLKQML AGAP9 c.742A>G p.M248V STSQEDPQFSVPPTANTPTPVCKLS[p.M248V]VRWSNL KLSVRWSNL,LSVRWSNLF,SVRWSNLFT,KLSVRWSNLF,SV SKCM FTSEKGSDPDKERKAPENHA RWSNLFTS,TPTPVCKLSV,CKLSVRWSNL,TPVCKLSVRW AGBL5 c.1260_1261 p.l420fs KLNSVWIMPQQSAGLEESAPDTIPP[p.I420fs]QREWR CFQKGLLHV,TIPPQREWR,FQKGLLHVR,RCLLCGPAW,LCG STAD insC CLLCGPAWTCFQKGLLHVRKQL* PAWTCF,REWRCLLCG,CGPAWTCFQK,DTIPPQREWR,CF QKGLLHVR,LLCGPAWTCF,WRCLLCGPAW,REWRCLLCGP AGMAT c.937G>A p.V313M TGTPEIAGLTPSQALEIIRGCQGLN[p.V313M]MMGCDL MMGCDLVEV,IRGCQGLNM,RGCQGLNMM,GLNMMGCDLV, CRC VEVSPPYDLSGNTALLAANL NMMGCDLVEV,IIRGCQGLNM,IRGCQGLNMM AGPAT4 c.634G>A p.A212T ISMQVARAKGLPRLKHHLLPRTKGF[p.A212]TITV RTKGFTITV,FTITVRSLR,LPRTKGFTI,LLPRTKGFTI,RTKGFTI CRC RSLRNVVSAVYDCTLNFRNNEN TVR,KGFTITVRSL,GFTITVRSLR,LPRTKGFTIT AGRN c.3851_3853 p.1284_1285 GATSGAIAAGATARATTASRLPSSA[p.l284_1285 ASRLPSSAA,RLPSSAAPR,SSAAPRAPH,APRAPHPSH,LPSS KICH de|TGA VT>A VT>A]APRAPHPSHTSQPVAKTTAAPTTRRPPT AAPRA,RLPSSAAPRA,APRAPHPSHT AGXT2 c.1504C>T p.R502C FSQTFRIAPSMCITKPEVDFAVEVF[p.R502C] FAVEVFCSA,FCSALTQHM,VEVFCSALT,FAVEVFCSAL,CSA UCEC CSALTQHMERRAK* LTQHMER,VFCSALTQHM AHI1 c.909_910 p.K303fs DDEISSMEQSTEDSMQDDTKPKPKK[p.K303fs] KPKPKKNKK STAD insA NKKED* AHNAK c.12449C>T p.S4150F KAPKISMPEVDLNLKGPKMKGDVDV[p.S4150F]FLP KMKGDVDVF,KMKGDVDVFL,KGDVDVFLPK,PKMKGDVDVF BLCA KVEGDLKGPEVDIKGPKVDIDVP AHNAK c.15_16 p.5_6insE MEKEE[p.5_6insE]ETTRELLLPNWQGS KEEETTREL,EEETTRELL,KEEETTRELL,EEETTRELLL KIRC insGAG GSHGLTIAQRDDGV AHNAK c.3658G>A p.V1220I ISMPDVDLHLKGPKVKGDVDVSVPK[p.V1220I]IEG IEGEMKVPDV,VPKIEGEMKV CLL EMKVPDVEIKGPKMDIDAPDVEV AHNAK c.6341C>G p.A2114G PDVSLEGPEGKLKGPKLKMPEMHFK[p.A2114G]GPKIS HFKGPKISM,MHFKGPKISM,PEMHFKGPKI CLL MPDVDLHLKGPKVKGDVDVSL AHNAK c.8665G>C p.D2889H LKGPEVDLKGPKVDIDVPDVNVQGP[p.D2889]HWHL VQGPHWHLK,NVQGPHWHL,NVQGPHWHLK,HWHLKM BLCA KMPKMKMPKFSMPGFKAEGPEV PKMK,VQGPHWHLKM AHNAK2 c.3643C>T p.P1215S APKVEADVSLPSMQGDLKTTDLSIQ[p.P1215S]SPSADL SPSADLEVH KIRP EVHAGQVDVKLLEGHVPEGA AHNAK2 c.4918C>A p.L1640M PDVKMSLSSMEVDVQAPRAKLDGAQ[p.L1640M]MEG AQMEGDLSL,QMEGDLSLA,RAKLDGAQM,AQMEGDLSLA TGCT DLSLADKAVTAKDSKFKMPKFKM AHNAK2 c.6497C>T p.S2166F LANKDLTTKDSKFKMPKFKMPSFGV[p.S2166F]FA KMPSFGVFA,SFGVFAPGK,FKMPSFGVF,GVFAPGKSI,MPS KIRP PGKSIEASVDVSPPKVEADMSLPS FGVFAP,PSFGVFAPGK,KFKMPSFGVF,MPSFGVFAPG,FKMPSFGVFA AICDA c.391C>G p.R131G LRIFTARLYFCEDRKAEPEGLRRLH[p.R131]GAGV RLHGAGVQI,GLRRLHGAGV,RLHGAGVQIA,RRLHGAGVQI, LUSC QIAIMTFKDYFYCWNTFVENHE LHGAGVQIAI,HGAGVQIAIM AICDA c.431A>T p.Y144F RKAEPEGLRRLHRAGVQIAIMTFKD[p.Y144F]FF IMTFKDFFY,MTFKDFFYC,FFYCWNTFV,TFKDFFYCW,DFF GBM YCWNTFVENHERTFKAWEGLHENS YCWNTF,IAIMTFKDF,AIMTFKDFF,KDFFYCWNT,AIMTFK DFFY,IAIMTFKDFF,MTFKDFFYCW,KDFFYCWNTF,DFFYCWNTFV AIDA c.740A>T p.K247M VDIELQKHVEKLTKGAAIFFEFKHY[p.K247M]MPK IFFEFKHYM,EFKHYMPKK,MPKKRFTST,FEFKHYMPK,KHY KIRC KRFTSTKCFAFMEMDEIKPGPIV MPKKRF,YMPKKRFTST,MPKKRFTSTK,FFEFKHYMPK,EFK HYMPKKR,AIFFEFKHYM,FKHYMPKKRF AK302879 c.572A>G p.Q191R AVSTQQQEEDRSSSCREAVLQWRLQ[p. AVLQWRLQR,QWRLQRTIK,RTIKEQALL,LQWRLQRTI,VLQ PRAD Q191R]RTIKEQALLNAHVTQVTESLKQVQLE WRLQRTI,EAVLQWRLQR,LQRTIKEQAL AK7 c.476C>T p.A159V SALSEEVSHFEKRKLFILLSTVMTW[p.A159V]VR LLSTVMTWV,VMTWVRSKA,TVMTWVRSK,MTWVRSKAL, GBM SKALDPEDSEVPFTEEDYRRRKSH LSTVMTWVR,ILLSTVMTWV,TVMTWVRSKA,VMTWVRS KAL,STVMTWVRSK,LLSTVMTWVR AK8 c.728A>C p.D243A KLLEYHRNIVRVIPSYPKILKVISA[p.D243A]AQ KILKVISAA,VISAAQPCV,AQPCVDVFY,AAQPCVDVF,KVIS GBM PCVDVFYQALTYVQSNHRTNAPFT AAQPCV,AAQPCVDVFY,SAAQPCVDVF AKAP12 c.3844G>A p.E1282K ILSKTEGTQEADQYADEKTKDVPFF[p.E1282K]KG KTKDVPFFK,KDVPFFKGL,KTKDVPFFKG CRC LEGSIDTGITVSREKVTEVALKGE AKAP13 c.8353de|A p.K2785fs QAPASTSASTRLFGLTKPKEKKEKK[p.K2785fs]RR ALSPVMVPR,KRRTKPAAL,RTKPAALSP,RQKYQQRVK,QQRVKRSSA, STAD TKPAALSPVMVPRQKYQQRVKRSSADPLPLC* RVKRSSADP,RSSADPLPL,KPAALSPVM,EKKRRT KPA,YQQRVKRSS,VKRSSADPL,RTKPAALSPV,AALSPVMV PR,RQKYQQRVKR,RVKRSSADPL,MVPRQKYQQR,KPAALS PVMV,VPRQKYQQRV,KKRRTKPAAL,TKPAALSPVM,YQQRVKRSSA, KRSSADPLPL,SPVMVPRQKY AKAP9 c.10444C>A p.L3482I RRILYQNLNEPTTWSLTSDRTRNWV[p.L3482I]IQ RTRNWVIQQ,SDRTRNWVI,RNWVIQQKI,RTRNWVIQQK CRC QKIEGETKESNYAKLIEMNGGGTG AKAP9 c.11229de|G p.M3743fs YLLLLLGGFQECEDATLALLARMGG[p. RMGGSQLSR,LARMGGSQL,RMGGSQLSRI,LLARMGGSQL STAD M3743fs]SQLSRI* AKD1 c.3625de|A p.R1209fs DMKAKIRVDTIAKRRAELILERDKK[p.R1209fs] MLLEMMKRL,TMMILKTSL,NLKKTMMIL,RMLLEMMKR,E STAD GGRMLLEMMKRLVRKNLKKT MMKRLVRK,RLVRKNLKK,MMILKTSLK,TSLKMSFQK,KMS MMILKTSLKMSFQKMRKR* FQKMRK,MSFQKMRKR,KRLVRKNLK,KNLKKTMMI,LKKT MMILK,KTMMILKTS,KTSLKMSFQ,SLKMSFQKM,MKRLV RKNL,MILKTSLKM,KGGRMLLEM,RKNLKKTMM,LKTSLK MSF,MLLEMMKRLV,MMILKTSLKM,NLKKTMMILK,TMM ILKTSLK,KTSLKMSFQK,KMSFQKMRKR,GGRMLLEMMK, MMKRLVRKNL,MKRLVRKNLK,KRLVRKNLKK,KTMMILKTS L,SLKMSFQKMR,ILKTSLKMSF,LERDKKGGRM,KKGGRML LEM,RMLLEMMKRL,RKNLKKTMMI,TSLKMSFQKM AKNAD1 c.1859A>G p.K620R AEMTAPSPSCAFCRRLLEWKQNVEK[p.K620R]RGHG NVEKRGHGR,RGHGRINCGR HNSC RINCGRFSIVLHEKAPHSDSTP AKT1 c.49G>A p.E17K MSDVAIVKEGWLHKRG[p.E17K]KYIKTWRPR WLHKRGKYI,LHKRGKYIK,RGKYIKTWR,KYIKTWRPR,GWL BRCA,CESC, YFLLKNDGTFIGYKERP HKRGKY,WLHKRGKYIK,KYIKTWRPRY,HKRGKYIKTW THCA AKT2 c.867C>G p.I289M EYLHSRDVVYRDIKLENLMLDKDGH[p.I289M]MKI LMLDKDGHM,HMKITDFGL,MLDKDGHMK,MLDKDGHM BRCA TDFGLCKEGISDGATMKTFCGTP KI,LMLDKDGHMK ALAS1 c.904G>C p.G302R PRVCGAVMDTLKQHGAGAGGTRNIS[p.G302R]RTS GTRNISRTS,ISRTSKFHV,RTSKFHVDL,RNISRTSKF,NISRTS KIRC KFHVDLERELADLHGKDAALLFS KFHV,GTRNISRTSK,TRNISRTSKF ALB c.881C>T p.S294L CCHGDLLECADDRADLAKYICENQD[p.S294L] YICENQDLI,KYICENQDL,NQDLISSKL,CENQDLISS,KYICEN CRC LISSKLKECCEKPLLEKSHCIAEVEN QDLI,AKYICENQDL ALDH1A2 c.253C>T p.R85C PATGEQVCEVQEADKADIDKAVQAA[p.R85C]CLAFS CLAFSLGSV,QAACLAFSL,AVQAACLAF,VQAACLAFSL,KAV PRAD LGSVWRRMDASERGRLLDKLA QAACLAF,CLAFSLGSVW ALDH1L1 c.2608G>A p.A870T KALYVSDKLQAGTVFVNTYNKTDVA[p.A870T]TPFGG VATPFGGFK,DVATPFGGF,NKTDVATPF,DVATPFGGFK,YN CRC FKQSGFGKDLGEAALNEYLRV KTDVATPF,TDVATPFGGF ALDH2 c.858de|G p.L286fs TEIGRVIQVAAGSSNLKRVTLELGG[p.L286fs]RAPTS SMMSLWSGA,MMSLWSGAL,SLGWSGTPL,VVGALLLTV,K STAD SCQMPIWIGPWNRPTSPCSSTRASAAVPAPGPSCRRTS LSLRRSSA,ATSTRGSKR,QMPIWIGPW,STRASAAVP,RTSM MMSLWSGALPGPSLGWSGTPLIARPSRGRRWMKLSLR MSLWS,IARPSRGRR,PSRGRRWMK,RGRRWMKLS,RWM RSSATSTRGSKRGRSCCVVGALLLTVVTSSS KLSLRR,SLRRSSATS,SATSTRGSK,STRGSKRGR,RGRSCCVV PLCLEMCRMA* G,SSSPLCLEM,PIWIGPWNR,SSTRASAAV,TVVTSSSPL,RP TSPCSST,GPSCRRTSM,RPSRGRRWM,LELGGRAPT,RAPTS SCQM,CRRTSMMSL,RRTSMMSLW,SLWSGALPG,SGALP GPSL,LGWSGTPLI,GRRWMKLSL,RSCCVVGAL,MPIWIGP WN,SMMSLWSGAL,SLGWSGTPLI,CVVGALLLTV,VVGALL LTVV,SSATSTRGSK,CQMPIWIGPW,STRASAAVPA,RASAA VPAPG,SCRRTSMMSL,RTSMMSLWSG,TSMMSLWSGA,R PSRGRRWMK,RGRRWMKLSL,GSKRGRSCCV,RGRSCCVV GA,RSCCVVGALL,MPIWIGPWNR,LIARPSRGRR,SATSTRG SKR,CSSTRASAAV,LTVVTSSSPL,APTSSCQMPI,GPWNRPT SPC,SPCSSTRASA,GPSCRRTSMM,GRAPTSSCQM,CRRTS MMSLW,MSLWSGALPG,WSGALPGPSL,GALPGPSLGW,I ARPSRGRRW,MKLSLRRSSA,GRSCCVVGAL,TSSSPLCLEM, LELGGRAPTS,SPLCLEMCRM ALDH3A1 c.1685de|C p.P562fs ETFSHRRSCLVRPLMNDEGLKVRYP[p.P562fs]R GLKVRYPRA,KVRYPRARP,EGLKVRYPR,GLKVRYPRAR,KV STAD ARPR* RYPRARPR ALG2 c.905C>A p.S302Y NVEHYQELKKMVQQSDLGQYVTFLR[p.S302Y]YFSD TFLRYFSDK,QYVTFLRYF,RYFSDKQKI,GQYVTFLRY,YVTFL CRC KQKISLLHSCTCVLYTPSNEHF RYFS,LGQYVTFLRY,VTFLRYFSDK,FLRYFSDKQK,GQYVTFLRYF ALKBH1 c.409A>G p.K137E WHWVKQCLKLYSQKPNVCNLDKHMS[p.K137E]EEE SEEETQDLW,HMSEEETQDL,MSEEETQDLW LUAD TQDLWEQSKEFLRYKEATKRRPR ALPK2 c.1067de|T p.L356fs ECSDVMTDYSNAVWQRNLLGTEHVF[p.L356fs]Y* LLGTEHVFY,NLLGTEHVFY STAD ALPK2 c.1568de|A p.K523fS LLSGESENSGMSQCWETAADKRVGG[p.K523fs]RT RVGGRTYGA,RTYGARGVQ,RVGGRTYGAR,RTYGARGVQ UCEC YGARGVQGNLPG* G,TAADKRVGGR,ADKRVGGRTY ALPK2 c.157G>A p.D53N DAVLRCIISGQPKPEVTWYKNGQAI[p.D53N]NGS NGSGIISNY,GQAINGSGI,INGSGIISNY,GQAINGSGII LUSC GIISNYEFFENQYIHVLHLSCCT ALPPL2 c.92G>C p.W31S VLLLLGLRLQLSLGIIPVEEENPDF[p.W31S]SN SNRQAAEAL,FSNRQAAEAL TGCT RQAAEALGAAKKLQPAQTAAKNLI ALX4 c.377G>A p.R126Q PPPQPQPQQQQPQPQPPAQPHLYLQ[p.R126Q]QG YLQQGACKT,HLYLQQGACK,LQQGACKTPP BLCA ACKTPPDGSLKLQEGSSGHSAALQ AMBN c.674C>A p.S225Y QGPSLPGLDFADPQGSTIFQIARLI[p.S225Y]YH IFQIARLIY,FQIARLIYH,ARLIYHGPM,TIFQIARLIY,IARLIYH UCEC GPMPQNKQSPLYPGMLYVPFGANQ GPM,IYHGPMPQNK,FQIARLIYHG AMDHD1 c.7A>G p.S3G MA[p.53G]GGHSLLLENAQQVVLVCARGERFLAR MAGGHSLLL ACC AMPH c.874C>T p.R292W PSPLPSPTASPNHTLAPASPAPARP[p.R292W]WS APARPWSPS,RPWSPSQTRK CRC PSQTRKGPPVPPLPKVTPTKELQQ ANAPC1 c.1609A>G p.T537A PGLPAPSLTMSNTMPRPSTPLDGVS[p.T537A]APK VSAPKPLSK,APKPLSKLL,GVSAPKPLSK PAAD,PRAD PLSKLLGSLDEVVLLSPVPELRD ANK2 c.1358A>G p.N453S TESGLTPIHVAAFMGHLNIVLLLLQ[p.N453S]SG VLLLLQSGA,LQSGASPDV,LLQSGASPDV,LQSGASPDVT KIRC ASPDVTNIRGETALHMAARAGQVE ANK2 c.9227A>T p.Q3076L DDEAFEARVKEEEQKIFGLMVDRQS[p.Q3076L]LG GLMVDRQSL,RQSLGTTPD,LMVDRQSLGT,FGLMVDRQSL, LUAD TTPDTTPARTPTEEGTPTSEQNPF RQSLGTTPDT ANK3 c.3966T>A p.D1322E LATQLYRELICVPYMAKFVVFAKMN[p.D1322E]E KMNEPVESS,VVFAKMNEPV,KMNEPVESSL,EPVESSLRCF TGCT PVESSLRCFCMTDDKVDKTLEQQEN ANKDD1A c.71G>A p.R24H MQEELAWETDGLLPLERQLHEAA[p.R24H]HQNN HEAAHQNNV,AHQNNVGRM,EAAHQNNVGR,LERQLHEA UCEC VGRMQELIGRRVNTRARNHVGR AH,RQLHEAAHQN,AAHQNNVGRM ANKFN1 c.840G>T p.M280I YRLYRRMKTGFEHARAPEMPTNVCL[p.M280I]IVT EMPTNVCLI,LIVTSSTSL,MPTNVCLIV,CLIVTSSTSL,EMPTN LUSC SSTSLTVSFQEPLSVNAAVVTRY VCLIV,IVTSSTSLTV,MPTNVCLIVT,PEMPTNVCLI ANKLE1 c.1930_1933 p.C644fs TAAPISGFRRGVCVCVCVCVCVCVC[p.C644fs]VCV CVCREHPGR,REHPGRSPP,CVCVCVCVCR,REHPGRSPPG TGCT de|TGTT CVCREHPGRSPPG* ANKLE1 c.1932_1933 p.C644fs TAAPISGFRRGVCVCVCVCVCVCVC[p.C644fs]VCV RWYCWRGSK,CYRWYCWRG,QAERGLCYR,LCYRWYCWR, TGCT de|TT CVCVGSTQADLPQAERGLCYRWYCWRGSK* PQAERGLCY,AERGLCYRW,RGLCYRWYCW,GLCYRWYCW R,LPQAERGLCY,AERGLCYRWY ANKMY1 c.905A>T p.N302I KELDARIFLNEIPPFVEDGEPWFII[p.N302I]IE FIIIETPLL,IIIETPLLV,IIETPLLVK,IETPLLVKI,FIIIETPLLV, THCA TPLLVKIQKQTYKFRNKPAHTSWN IIIETPLLVK,WFIIIETPLL,GEPWFIIIET ANKRDll c.1106A>G p.K369R KDEYEFDEDDEQDRVPPVDDKHLLK[p.K369R]RD HLLKRDYRK,KHLLKRDYR,KHLLKRDYRK TGCT YRKETKSNSFISIPKMEVKSYTKN ANKRDll c.6044A>C p.Y2015S SPKRFCPADPLHSAAPGPFSASEAP[p.Y2015S]S SASEAPSPA,EAPSPAPPA,SPAPPASPA,FSASEAPSPA,SPAP TGCT PAPPASPAPYALPVAEPGLEDVKDG PASPAP,SEAPSPAPPA ANKRD12 c.1879G>A p.E627K HKEKSKHQKDFHLEFGEKSNAKIKD[p.E627K]KD KSNAKIKDK,KDKDHSPTF,IKDKDHSPTF BLCA HSPTFENSDCTLKKMDKEGKTLKK ANKRD12 c.2161G>C p.E721Q WKENFFKSDETEDLFLNMEHESLTL[p.E721Q]QK LQKKSKLEK,TLQKKSKLEK CESC KSKLEKNIKDDKSTKEKHVSKERN ANKRD32 c.2996C>A p.T999N SEFILASKGLTHLNELLMACKSHKE[p.T999N]N KSHKENTSV,NTSVHTDWL,NTSVHTDWLL,KSHKENTSVH, BLCA TSVHTDWLLDLYAGNIKTLQKLPHI KENTSVHTDW ANKRD36 c.1010C>G p.P337R TSDKDDSVSNTATEIKDEQKSGTVL[p.P337R]RA KSGTVLRAV,EQKSGTVLR,QKSGTVLRAV CLL VEQCLNRSLYRPDAVAQPVTENEF ANKRD36 c.1133A>G p.K378R VAQPVTENEFSLESEIISKLYIPKR[p.K378R]R RIISPRSIK,LYIPKRRII,KLYIPKRRI,KRRIISPRS,IPKRRIISP, KIRC IISPRSIKDVLPPVEEAVDRCLYLL RRIISPRSI,ISKLYIPKRR,KLYIPKRRII,KRRIISPRSI, IPKRRIISPR ANKRD36 c.3040G>T p.D1014Y SEKPPGLKATSDEKDSVLNIARGKK[p.D1014Y]Y RGKKYGEKTR,KKYGEKTRTV CLL GEKTRTVSSQKPPTLKATSDEEDSV ANKRD36 c.3431T>C p.M1144T KSRTVSSPKQPALKAICDKEDSVPN[p.M1144T]TATE SVPNTATEK,KEDSVPNTA,SVPNTATEKK,KEDSVPNTAT CESC KKDEQISGTVSCQKQPALKATS ANKRD36C c.1313A>G p.H438R LEKDTIKNQNLEKKYLKDFEIVKRK[p.H438R] IVKRKREDL PAAD,PRAD REDLQKA ANKRD50 c.1909G>A p.V637M WTALRSAAWGGHTEVVSALLYAGVK[p.V637M]MD ALLYAGVKM,SALLYAGVKM TGCT CADADSRTALRAAAWGGHEDIVLN ANKRD6 c.1435C>T p.R479C TQHQMRVLDKLMVERLSAERTECLN[p.R479C]CL CLQQHSDTEK,AERTECLNCL CRC QQHSDTEKHEGEKRQISLVDELKT ANO2 c.1000C>T p.R334C PLHDGEYDSPEDDMNDRKLLYQEWA[p.R334C]CY YQEWACYGV,WACYGVFYK,ACYGVFYKF,LLYQEWACY,E GBM GVFYKFQPIDLIRKYFGEKIGLYF WACYGVFY,QEWACYGVF,LYQEWACYGV,YQEWACYGVF, WACYGVFYKF,KLLYQEWACY,EWACYGVFYK,QEWACYGVFY ANO3 c.121G>T p.A41S GMNISKSEITKETSLKPSRRSLPCL[p.A41S]SQ LSQSYAYSK,SLPCLSQSY,SLPCLSQSYA,CLSQSYAYSK,RSLP LUAD SYAYSKSLSQSTSLFQSTESESQA CLSQSY,SQSYAYSKSL,LPCLSQSYAY ANO3 c.2868G>T p.M956I IAYLIPDVPKGLHDRIRREKYLVQE[p.M956I]IM LVQEIMYEA,KYLVQEIMY,IMYEAELEH,REKYLVQEI,EKYLV CESC YEAELEHLQQQRRKSGQPVHHEWP QEIM,QEIMYEAEL,YLVQEIMYEA,IMYEAELEHL,RREKYLV QEI,REKYLVQEIM,EKYLVQEIMY,VQEIMYEAEL ANXA6 c.692G>A p.R231Q RSKQHLRLVFDEYLKTTGKPIEASI[p.R231Q]Q IQGELSGDF,IEASIQGEL HNSC GELSGDFEKLMLAVVKCIRSTPEYF AOC3 c.237_238 p.L79fs QSQLFADLSREELTAVMRFLTQRLG[p.L79fs]A GQLCLLSGV,CLLSGVAAA,RLLWQATPA,RFLTQRLGA,FLT STAD insG RAGGCSPGPALGQLCLLSGVAAASQGCSPGSLG QRLGAR,LWQATPAQR,SPGPALGQL,GPALGQLCL,CPGGT QGEPPTCPGGTGHRLLWQATPAQRE* GHRL,TQRLGARAG,SQGCSPGSL,FLTQRLGARA,RFLTQRL GAR,LLWQATPAQR,GPALGQLCLL,CPGGTGHRLL,MRFLT QRLGA,GQLCLLSGVA,HRLLWQATPA AOX1 c.1520C>T p.A507V GRHWNEQMLDIACRLILNEVSLLGS[p.A507V]V LLGSVPGGK,NEVSLLGSV,LLGSVPGGKV,SLLGSVPGGK,SV GBM PGGKVEFKRTLIISFLFKFYLEVSA PGGKVEFK,GSVPGGKVEF AP1G1 c.2168G>T p.R723L NDIAAGIPSITAYSKNGLKIEFTFE[p.R723L]L ELSNTNPSV,LKIEFTFEL,FELSNTNPS,IEFTFELSN,GLKIEFTF LUAD SNTNPSVTVITIQASNSTELDMTDF EL,IEFTFELSNT,FELSNTNPSV AP1G2 c.727G>A p.D243N PQLVHILRTLVTMGYSTEHSISGVS[p.D243N]N GVSNPFLQV,NPFLQVQIL,SISGVSNPF,SISGVSNPFL,HSISGVS HNSC PFLQVQILRLLRILGRNHEESSETM NPF,NPFLQVQILR,VSNPFLQVQI AP3S1 c.121_124 p.K41fs LSKFYQPYSEDTQQQIIRETFHLVS[p.K41fs]E LVSEMKMFV,TFHLVSEMK,ETFHLVSEM,FHLVSEMKM,HL PAAD de|AAGA MKMFVIS* VSEMKMF,SEMKMFVIS,RETFHLVSE,HLVSEMKMFV,LVS EMKMFVI,ETFHLVSEMK,RETFHLVSEM,FHLVSEMKMF AP4B1 c.826C>T p.R276W VVMGATKLFLILAKMFPHVQTDVLV[p.R276W]W VQTDVLVWV,VLVWVKGPL,QTDVLVWVK,HVQTDVLVW, PRAD VKGPLLAACSSESRELCFVALCHVR VLVWVKGPLL,HVQTDVLVWV,VQTDVLVWVK,DVLVWVKGPL APBA1 c.1870G>A p.E624K LIAQSIGQAFSVAYQEFLRANGINP[p.E624K]K FLRANGINPK,GINPKDLSQK,NPKDLSQKEY CRC DLSQKEYSDLLNTQDMYNDDLIHFS APBA1 c.2190G>T p.K730N QIMSINGTSLVGPLSTCQSIIKGL[p.K730N]NN GLNNQSRVK,KGLNNQSRVK,IIKGLNNQSR CRC QSRVKLNIVRCPPVTTVLIRRPDL APBB2 c.729_730 p.T243fs EDGQVATVSSSPETKKDHPKTGAKT[p.T243fs]R GAKTRLCTA,KTRLCTAPD,KTRLCTAPDP,HPKTGAKTRL LUAD insC LCTAPDPEPGTER* APC c.2540de|A p.E847fs PYLNTTVLPSSSSSRGSLDSSRSEK[p.E847fs] SSRSEKIEV,EVWRENAEL,EVWRENAELV,SSRSEKIEVW,IE CRC IEVWRENAELV* VWRENAEL APC c.4060de|T p.F1354fs PRTKSSRLQGSSLSSESARHKAVEF[p.F1354fs]L CLADVLLSV,VLLSVHLIV,LLSVHLIVL,TMFRRPHSC,SVHLIV CRC QERNLPPKVVLRHPKVHLNTMFRRPHSCLADVLLSVHLI LRV,KVHLNTMFR,LSVHLIVLR,VVRLPAPFR,RVVRLPAPF,K VLRVVRLPAPFRVNHAVEW* VVLRHPKV,VLRHPKVHL,MFRRPHSCL,VLRVVRLPA,KAVE FLQER,NLPPKVVLR,HLIVLRVVR,DVLLSVHLI,HPKVHLNT M,RPHSCLADV,APFRVNHAV,ARHKAVEFL,RNLPPKVVL,F RVNHAVEW,LPAPFRVNH,VEFLQERNL,QERNLPPKV,ADV LLSVHL,TMFRRPHSCL,VLLSVHLIVL,SVHLIVLRVV,HLIVLR VVRL,FLQERNLPPK,KVHLNTMFRR,RVVRLPAPFR,SARHK AVEFL,RNLPPKVVLR,MFRRPHSCLA,VVRLPAPFRV,LLSVHLIVLR, DVLLSVHLIV,LSVHLIVLRV,HPKVHLNTMF,RPHSCL ADVL,LPAPFRVNHA,NTMFRRPHSC,LQERNLPPKV,RHPK VHLNTM,HLNTMFRRPH,CLADVLLSVH,LRWRLPAPF,ADVLLSVHLI APOB c.128C>T p.A43V LLLLLAGARAEEEMLENVSLVCPKD[p.A43V]VTRFKH VTRFKHLRK,LVCPKDVTR,DVTRFKHLR,VTRFKHLRKY,SLV CRC LRKYTYNYEAESSSGVPGTA CPKDVTR,DVTRFKHLRK,LVCPKDVTRF APOB c.2917C>A p.L973M TKTEVIPPLIENRQSWSVCKQVFPG[p.L973M]MN GMNYCTSGA,KQVFPGMNY,MNYCTSGAY,GMNYCTSGA LUAD YCTSGAYSNASSTDSASYYPLTGD Y,SVCKQVFPGM,CKQVFPGMNY,KQVFPGMNYC APOB c.9306C>A p.F3102L FLSPSAQQASWQVSARFNQYKYNQN[p.F3102L]L NQYKYNQNL,YKYNQNLSA,NLSAGNNENI,QYKYNQNLSA, UCEC SAGNNENIMEAHVGINGEANLDFLN FNQYKYNQNL,NQYKYNQNLS,YKYNQNLSAG,LSAGNNENIM APOB c.9406C>T p.R3136C MEAHVGINGEANLDFLNIPLTIPEM[p.R3136C]C TIPEMCLPY,PEMCLPYTI,LTIPEMCLPY,PEMCLPYTII,IPLTI CRC LPYTIITTPPLKDFSLWEKTGLKEF PEMCL,IPEMCLPYTI APOBR c.2519G>T p.R840L SQVEAFESREGGPWGGRVEAEESAG[p.R840L]V VEAEESAGV,VEDSCGLDPA LUAD EDSCGLDPAGSQTARAEGMGAMVEA APOD c.344C>T p.S115L IEGEATPVNLTEPAKLEVKFSWFMP[p.S115L]LA FMPLAPYWI,WFMPLAPYW,KFSWFMPLA,SWFMPLAPY, CESC PYWILATDYENYALVYSCTCIIQL MPLAPYWIL,VKFSWFMPL,FSWFMPLAPY,FMPLAPYWIL, SWFMPLAPYW,WFMPLAPYWI,EVKFSWFMPL,VKFSWF MPLA,MPLAPYWILA APOE c.388T>C p.C130R EETRARLSKELQAAQARLGADMEDV[p.C130R]R RGRLVQYRG,MEDVRGRLV,DVRGRLVQYR ACC GRLVQYRGEVQAMLGQSTEELRVRL APOOL c.412A>C p.I138L PKMGVITVSGLAGLVSARKGSKFKK[p.I138L]L KLTYPLGLA,KFKKLTYPL,GSKFKKLTY,KKLTYPLGL,LTYPLGL CLL TYPLGLATLGATVCYPVQSVIIAKV ATL,KFKKLTYPLG,KGSKFKKLTY,SKFKKLTYPL,FKKLTYPLGL APPL1 c.2002C>T p.R668W ERVKEKQQKELNKQKQIEKDLEEQS[p.R668W]W SWLIAASSR,LEEQSWLIA,EEQSWLIAA,QSWLIAASSR,IEK CRC LIAASSRPNQASSEGQFVVLSSSQS DLEEQSW,LEEQSWLIAA,EEQSWLIAAS,KDLEEQSWLI AQP10 c.782A>T p.Q261L SAGNGWWWVPVVAPLVGATVGTATY[p.Q261L]L GTATYLLLV,ATYLLLVAL,ATVGTATYL,TVGTATYLL,GTATYL LUAD LLVALHHPEGPEPAQDLVSAQHKAS LLVA,ATYLLLVALH,ATVGTATYLL AQP2 c.203A>C p.N68T QIAMAFGLGIGTLVQALGHISGAHI[p.N68T]TPAV HITPAVTVA,SGAHITPAV,TPAVTVACL,AHITPAVTV,HISG KIRP TVACLVGCHVSVLRAAFYVAAQ AHITPA,ITPAVTVACL,TPAVTVACLV,AHITPAVTVA AQPEP c.925G>A p.A309T KEDVNGSKWTVTTFSTTPHMPTYLV[p.A309T]TFVI HMPTYLVTF,PTYLVTFVI,TYLVTFVIC,LVTFVICDY,MPTYLVTFV, CRC CDYDHVNRTERGKEIRIWARKD HMPTYLVTFV,PHMPTYLVTF,YLVTFVICDY,MPTYLVTFVI ARAP3 c.3677G>T p.R1226L ASLLLKKVPLAQAGCLFTGIRRESP[p.Rl226L]L GIRRESPLV,TGIRRESPL,RRESPLVGL,RESPLVGLL,FTGIRRE LUAD VGLLRCREEPPRLLGSRFQERFFLL SPL,IRRESPLVGL ARF4 c.446G>A p.R149H FANKQDLPNAMAISEMTDKLGLQSL[p.R149H]H SLHNRTWYV,HNRTWYVQA,QSLHNRTWY,LQSLHNRTW,QS CRC NRTWYVQATCATQGTGLYEGLDWLS LHNRTWYV,LQSLHNRTWY,KLGLQSLHNR,GLQSLHNRTW ARFGAP2 c.113G>A p.S38N LFKRLRAVPTNKACFDCGAKNPSWA[p.S38N]N SWANITYGV,NPSWANITY,WANITYGVF,AKNPSWANI,ANITYGVF PRAD ITYGVFLCIDCSGVHRSLGVHLSFI L,SWANITYGVF,GAKNPSWANI,KNPSWANITY,NI TYGVFLCI,WANITYGVFL ARFGAP3 c.896de|A p.N299fs SLRLAYKDLEIQMKKDEKMNISGKK[p.N299fs] KMLTQTDSA,EIAEVLFHI,KMNISGKKM,DSAWDLEIA,MLT PRAD MLTQTDSAWDLEIAEVLFHIQ* QTDSAW,TQTDSAWDL,LEIAEVLFH,WDLEIAEVL,QTDSA WDLEI,SAWDLEIAEV,KMNISGKKML,EKMNISGKKM,KK MLTQTDSA,KMLTQTDSAW,LEIAEVLFHI,WDLEIAEVLF ARFGEF1 c.4654_4655 p.P1552fs LDIFKTTIPHALLTWRPNSGETAPP[p.Pl552fs]T ETAPPTSIS,GETAPPTSI,ETAPPTSISC STAD insC SISCK* ARFGEF1 c.4894G>A p.D1632N KFPEQKLFAALLIKCVVQLELIQTI[p.D1632N] ELIQTINNI,LIQTINNIV,QTINNIVFF,IQTINNIVF,TINNIVFFP CRC NNIVFFPATSKKEDAENLAAAQRDAV A,ELIQTINNIV,IQTINNIVFF,LIQTINNIVF,LELIQTINNI ARFIP2 c.257G>T p.R86L GLIPTGSGRHPSHSTTPSGPGDEVA[p.R86L]L VALGIAGEK,ALGIAGEKF,DEVALGIAG,VALGIAGEKF,DEVAL LUAD GIAGEKFDIVKKWGINTYKCTKQLL GIAGE ARHGAP24 c.103A>G p.T35A NPQQGQGRQNAIKCGWLRKQGGFVK[p.T35A]A KAWHTRWFV,AWHTRWFVL,GFVKAWHTR,RKQGGFVKA, TGCT WHTRWFVLKGDQLYYFKDEDETKPL KQGGFVKAW,FVKAWHTRW,VKAWHTRWF,AWHTRWF VLK,GFVKAWHTRW,KAWHTRWFVL,FVKAWHTRWF,RKQGGFVKAW ARHGAP32 c.3757G>A p.E1253K LEFADKSPTPPNLPSDKIYPPSGSP[p.El253K] SPKENTSTA,KENTSTATM,KIYPPSGSPK,SPKENTSTAT,KENT CRC KENTSTATMTYMTTTPATAQMSTKEA STATMT ARHGAP36 c.382C>T p.R128C GQQRAVSHKTFGISLEEVLVNEFTR[p.R128C] LVNEFTRCK,FTRCKHLEL,CKHLELTAT,NEFTRCKHL,VLVNE CRC CKHLELTATMQVEEATGQAAGRRRGN FTRCK,CKHLELTATM ARHGAP36 c.440C>T p.A147V VNEFTRRKHLELTATMQVEEATGQA[p.A147V] VGRRRGNVV,VEEQTGQAV,VGRRRGNVVR CRC VGRRRGNVVRRVFGRIRRFFSRRRNE ARHGAP36 c.47C>A p.P16H MGGCIPFLKAARALC[p.P16H]HRIMPPL KAARALCHR,AARALCHRI,RALCHRIMP,LKAARALCH,ARA LUAD LLLSAFIFLVSVLGGAPGH LCHRIM,HRIMPPLLL,ALCHRIMPPL,KAARALCHRI,AARAL CHRIM,RALCHRIMPP,HRIMPPLLLL ARHGAP5 c.2071A>T p.M691L ESLSFIGEFIGKIRTEASQIRKDKY[p.M691L] YLANLPFTL,KYLANLPFT,QIRKDKYLA,LANLPFTLI,DKYLAN GBM LANLPFTLILANQRDSISKNLPILRH LPF,SQIRKDKYL,RKDKYLANL,YLANLPFTLI,KYLANLPFTL,K DKYLANLPF,LANLPFTLIL ARHGAP5 c.2670de|T p.D890fs RAFLSEVQDTIPVQLVAVTDSQADF[p.D890fs] VTDSQADFL,FLKMRLSKS,DFLKMRLSK,VTDSQADFLK,SQ CRC,STAD LKMRLSKS* ADFLKMRL,DSQADFLKMR ARHGAP9 c.409C>T p.R137C QQVSLAEGDRFLLLRKTNSDWWLAR[p.R137C]C SDWWLARCL,WLARCLEAPS BRCA LEAPSTSRPIFVPAAYMIEESIPSQ ARHGEF17 c.1844de|C p.A615fs VQEARQVFEKIQRMGAQQDDGSDAP[p.A615fs] LEQLTGQGM,QQDDGSDAPL STAD LEALTGQGM* ARHGEF5 c.1460A>G p.E487G PISLLGSFLTEESPDKEIDQNSQQE[p.E487G]GSRL GSRLRKGTV,SQQEGSRLRK KIRC RKGTVSSQGTEVVFASASVTPP ARHGEF5 c.4535de|C p.S1512fs EKLRWISALAMPREELDLLECYNSP[p.S1512fs] RMMNWHWRK,NWHWRKPTW,CYNSPRYSA,LLECYNSP STAD RYSAFEPTSPERMMNWHWRKPTW* R,YNSPRYSAF,LECYNSPRY,LLECYNSPRY,MMNWHWRKP T,SAFEPTSPER,CYNSPRYSAF,RMMNWHWRKP,DLLECYN SPR,SPRYSAFEPT,MNWHWRKPTW,FEPTSPERMM,SPERMMNWHW ARID1A c.1841C>T p.S614L QTAYSQQRFPPPQELSQDSFGSQAS[p.S614L]LA SLAPSMTSS,LAPSMTSSK,DSFGSQASL,SQASLAPSM,SLAP BLCA PSMTSSKGGQEDMNLSLQSRPSSL SMTSSK,DSFGSQASLA,GSQASLAPSM,SQASLAPSMT ARID1A c.3211de|A p.K107lfs KPLDLYRLYVSVKEIGGLTQVNKNK[p.K1071fs]N SMWAHQAVL,NLQPTSMWA,TSMWAHQAV,WAHQAVL STAD GGNLQPTSMWAHQAVLPAP* PA,LQPTSMWAH,TSMWAHQAVL,SMWAHQAVLP,MWAHQAVLPA ARID1A c.3972de|C p.Y1324fs STGAPQPNLMPSNPDSGMYSPSRYP[p.Y1324fs]RSS GQWMAHMAL,KMYTTSMAM,YTTSMAMPI,SMAMPILP STAD SSSSSNDMIPMAISSPPKAPLLAAPSPASRLQCINSN L,HMALLPSGT,LLSADQQAA,MALLPSGTK,KLPSLPLSK,PM SRITSGQWMAHMALLPSGTKGRCTACHTALGRGSLSSS AISSPPK,QWMAHMALL,MYSPSRYPR,KGRCTACHT,LSKM SCPQPSPSLPASNKLPSLPLSKMYTTSMAMPILPLPQLLL YTTSM,RTNFHSSLA,HPLAPMPSK,LAAPSPASR,TACHTAL SADQQAAPRTNFHSSLAETVSLHPLAPMPSKTCHHK* GR,HTALGRGSL,TTSMAMPIL,ETVSLHPLA,YPRSSSSSS,IP MAISSPP,SPASRLQCI,LPASNKLPS,LPSLPLSKM,MPILPLP QL,APRTNFHSS,QQAAPRTNF,SSSNDMIPM,VSLHPLAPM, SSSSSSNDM,ISSPPKAPL,SRITSGQWM,MAHMALLPS,AH MALLPSG,RCTACHTAL,SNKLPSLPL,SKMYTTSMA,FHSSLA ETV,SSLAETVSL,AETVSLHPL,LPLPQLLLS,GQWMAHMAL L,AMPILPLPQL,LLLSADQQAA,WMAHMALLPS,KLPSLPLSK M,GMYSPSRYPR,HMALLPSGTK,CTACHTALGR,MYTTSM AMPI,IPMAISSPPK,RLQCINSNSR,KGRCTACHTA,ASNKLP SLPL,LSKMYTTSMA,TSMAMPILPL,RTNFHSSLAE,ITSGQ WMAHM,LLAAPSPASR,LSADQQAAPR,SSNDMIPMAI,YT TSMAMPIL,TVSLHPLAPM,YPRSSSSSSS,SPPKAPLLAA,APL LAAPSPA,CPQPSPSLPA,SPSLPASNKL,LPASNKLPSL,MPIL PLPQLL,APRTNFHSSL,SKMYTTSMAM,LPSLPLSKMY,SSSS SSSNDM,SSSSNDMIPM,ISSPPKAPLL,LAAPSPASRL,LQCI NSNSRI,SGQWMAHMAL,GRCTACHTAL,SSCPQPSPSL,K MYTTSMAMP,DQQAAPRTNF,QQAAPRTNFH,HSSLAETVSL, LAETVSLHPL,LPLPQLLLSA,AETVSLHPLA ARID1A c.5542de|G p.G1848fs VDCSDKLGRVQEFDSGLLHWRIGGG[p.G1848s] RQSCCLPGL,CLPGLTHPA,LSISRPTSR,ISRPTSRAR,RARQSCCLP, STAD TPLSISRPTSRARQSCCLPGLT LTHPAHQPL,RPTSRARQS,WRIGGGTPL,LPGLTHPA HPAHQPLGSM* H,GLTHPAHQPL,LLHWRIGGGT,SISRPTSRAR,HWRIGGGT PL,TSRARQSCCL,RARQSCCLPG,RPTSRARQSC,HPAHQPL GSM,RIGGGTPLSI,ARQSCCLPGL,RQSCCLPGLT ARID1A c.6415de|C p.P2139fs RLVLETLSKLSIQDNNVDLILATPP[p.P2139fs]S IALWCASSV,ALWCASSVT,WLRGTAWQL,GTAWQLVPL,IL STAD AAWRSCIALWCASSVTERTRCAGRWLWYCWPTWLRGTA ATPPSAA,AWRSCIALW,RWLWYCWPT,WLWYCWPTW,LWYCWPTWL, WQLVPLQCRRAVSATSWAS* RTRCAGRWL,RAVSATSWA,RCAGRWLWY, WYCWPTWLR,QLVPLQCRR,WPTWLRGTA,VPLQCRRAV,SAAW RSCIA,LATPPSAAW,AAWRSCIAL,LQCRRAVSA,RR AVSATSW,CIALWCASSV,WLWYCWPTWL,WLRGTAWQL V,CAGRWLWYCW,RWLWYCWPTW,TWLRGTAWQL,RTR CAGRWLW,LATPPSAAWR,LWCASSVTER,VTERTRCAGR, LWYCWPTWLR,SAAWRSCIAL,WPTWLRGTAW,ILATPPSA AW,AAWRSCIALW,TERTRCAGRW,RGTAWQLVPL,LQCR RAVSAT,CRRAVSATSW,RAVSATSWAS ARID3A c.1649_1650 p.G550fs NGIMYTGVLFAQPPAPTPTSAPNKG[p.G550fs]R QQRRRPGRK,AVHTLHIYL,GAVHTLHIY,WASGAVHTL,RPG CLL de|GA RRRRQQQQRRRPGRKHRNQRRPGWASGAVHTLHIYLK* WASGAV,NQRRPGWAS,AVHTLHIYLK,GWASGQVHTL,Q QQRRRPGRK,SGAVHTLHIY,RQQQQRRRPG ARID4A c.3462T>A p.D1154E LNVSKPQKLARSPARISPHIKDGEK[p.D1154E]EK HIKDGEKEK CLL HREKHPNSSPRTYKWSFQLNELDN ARL13B c.1073G>T p.R358L ETDRPSLESANGKKKTKKLRMKRNH[p.R358L]L KLRMKRNHL,RMKRNHLVE,LRMKRNHLV,KRNHLVEPL,KL LUAD VEPLNIDDCAPESPTPPPPPPPVGW RMKRNHLV,RMKRNHLVEP,MKRNHLVEPL,KKLRMKRNHL ARL16 c.16G>A p.G6R MRVAG[p.G6R]RRALSRGAELRVPGGAKHGMCLLLGA RVAGRRALS,MRVAGRRAL,RVAGRRALSR,AGRRALSRGA, SKCM RRALSRGAEL ARL6IP1 c.223A>T p.M75L GVVSLVFLIIYYLDPSVLSGVSCFV[p.M75L]L GVSCFVLFL,SGVSCFVLF,VLFLCLADY,LSGVSCFVL,VLSGVS MM FLCLADYLVPILAPRIFGSNKWTTE CFVL,VLFLCLADYL,LSGVSCFVLF,FVLFLCLADY ARMC3 c.1540G>A p.A514T LRSKNDEVRKHASWAVMVCAGDELT[p.A514T]TNEL TTNELCRLGA TGCT CRLGALDILEEVNVSGTRKNKF ARMC4 c.64G>A p.E22K MGVALRKLTQWTAAGHGTGIL[p.E22K]KITPL KITPLNEAI,AGHGTGILK,TGILKITPL,LKITPLNEA,ILKITPLNE SKCM NEAILKEIIVFVESFIYKHPQ A,AAGHGTGILK,LKITPLNEAI ARNTL c.1184C>T p.T395M GTSCYEYFHQDDIGHLAECHRQVLQ[p.T395M] RQVLQMREK,LQMREKITT,AECHRQVLQM,RQVLQMREKI, CRC MREKITTNCYKFKIKDGSFITLRSRW LQMREKITTN,MREKITTNCY ARPC1A c.636C>A p.F212L SKMPFGQLMSEFGGSGTGGVVVHGVS[p.F212L]L WVHGVSLSA,SLSASGSRL,GGWVHGVSL,SLSASGSRLA,GV LUSC SASGSRLAVVVSHDSTVSVADASKSV SLSASGSR,VSLSASGSRL,LSASGSRLAW ARPP21 c.1013G>A p.R338H SSSENELKWSDHQRAWSSTDSDSSN[p.R338H]HNLK HNLKPAMTK,SNHNLKPAM,SSNHNLKPAM CRC PAMTKTASFGGITVLTRGDSTS ARPP21 c.388de|A p.I130fs HNVEKQDIATYYCALWEVHSKLGKK[p.I130fs]S SLSLQINNL,MQMFPPSPL,RLEHTFVFL,FVFLRNFSL,FLRNF STAD RYLVPEQSLSLQINNLMQMFPPSPLFFFLQLLKQS SLML,LQINNLMQM,LFFFLQLLK,LMLLRYIGK,MLLRYIGKK, SRRLEHTFVFLRNFSLMLLRYIGKKRRA RNFSLMLLR,RATRFWDPR,RYLVPEQSL,QMFPPSPLF,MF TRFWDPRRGTP* PPSPLFF,RRLEHTFVF,VFLRNFSLM,HSKLGKKSR,KLGKKSR YL,LGKKSRYLV,KSRYLVPEQ,KQSSRRLEH,SRRLEHTF,RYI GKKRRA,IGKKRRATR,ATRFWDPRR,NFSLMLLRY,LLRYIGKKR, SPLFFFLQL,LLKQSSRRL,YIGKKRRAT,QINNLMQMF,HT FVFLRNF,SKLGKKSRY,LSLQINNLM,LRNFSLMLL,GKKRRA TRF,KKRRATRFW,FPPSPLFFF,PPSPLFFFL,KLGKKSRYLV,Y LVPEQSLSL,LMQMFPPSPL,FVFLRNFSLM,FLRNFSLMLL,S LSLQINNLM,PLFFFLQLLK,RLEHTFVFLR,SLMLLRYIGK,LML LRYIGKK,LQINNLMQMF,MQMFPPSPLF,QMFPPSPLFF,M FPPSPLFFF,RRLEHTFVFL,TFVFLRNFSL,VFLRNFSLML,KSR YLVPEQS,SSRRLEHTFV,HTFVFLRNFS,RATRFWDPRR,ATR FWDPRRG,HSKLGKKSRY,RNFSLMLLRY,FLQLLKQSSR,ML LRYIGKKR,LLRYIGKKRR,YIGKKRRQTR,FPPSPLFFFL,SPLFF FLQLL,SRYLVPEQSL,SLQINNLMQM,LKQSSRRLEH,KQSSR RLEHT,QSSRRLEHTF,SRRLEHTFVF,VPEQSLSLQI ARRB2 c.295A>C p.T99P LSFRKDLFIATYQAFPPVPNPPRPP[p.T99P]PR RPPPRLQDRL TGCT LQDRLLRKLGQHAHPFFFTVRMPL ARRDC4 c.235A>G p.T79A ALRLEAQGRATAAWGPSTCPRASAS[p.T79A]A RASASAAAL,ASASAAALA,SASAAALAV,CPRASASAA,ASA ACC AALAVFSEVEYLNVRLSLREPPAGE AALAVF,AAALAVFSEV,STCPRASASA,RASASAAALA,ASAS AAALAV,CPRASASAAA,SASAAALAVF ARSD c.701C>G p.A234G LGILTLAAGQTCGFFSVSARAVTGM[p.A234G]GGVG MGGVGCLFF,SARAVTGMG,GMGGVGCLF,GMGGVGCLF KIRC CLFFISWYSSFGFVRRWNCILM F,SARAVTGMGG,TGMGGVGCLF ARSD c.701_709 p.AGV234 LGILTLAAGQTCGFFSVSARAVTGM[p.AGV234de|] TGMGCLFFI,VTGMGCLFF,SARAVTGMG,AVTGMGCLF, KIRC de|CCGGC de| GCLFFISWYSSFGFVRRW GMGCLFFISW,MGCLFFISWY,RAVTGMGCLF,AVTGMGCLFF GTGG NCILMRNHDVTEQPMV ARSG c.391G>A p.V131I FAVTSVGGLPLNETTLAEVLQQAGY[p.V131I]ITG QQAGYITGI,EVLQQAGYI,LQQAGYITG,LQQAGYITGI,QQAGYI CRC IIGKWHLGHHGSYHPNFRGFDYY TGII,AGYITGIIGK,GYITGIIGKW,AEVLQQAGYI ART1 c.729de|C p.I243fs IWTCLGAPIKGYSFFPGEEEVLIPP[p.I243fs] LIPPLRPSK,EEEVLIPPL,VLIPPLRPSK,GEEEVLIPPL STAD LRPSK* ASB16 c.745A>G p.T249A QHVALYLEHGADVGLRTSQGETALN[p.T249A]AA ALNAACAGA,ETALNAACA,SQGETALNA,GETALNAAC,SQ ACC CAGAEGPGSCRRHQAAARRLLEAG GETALNAA,GETALNAACA ASCC1 c.619C>T p.H207Y QEEVLAKCSMDHGVDSSIFQNPKKL[p.H207Y]YL YLTIGMLVL,FQNPKKLYL,KLYLTIGML,LYLTIGMLV,IFQNP CESC TIGMLVLLSEEEIQQTCEMLQQCK KKLY,NPKKLYLTI,KKLYLTIGM,KLYLTIGMLV,YLTIGMLVLL, IFQNPKKLYL,LYLTIGMLVL,SIFQNPKKLY,KKLYLTIGML ASCC2 c.1094G>T p.R365L CDNIQGFIEEFLQIFSSLLQEKRFL[p.R365L]L LLQEKRFLL,FLLDYDALF,RFLLDYDAL,QEKRFLLDY,LDYDAL LUAD DYDALFPVAEDISLLQQASSVLDET FPV,SLLQEKRFLL,FLLDYDALFP,LLDYDALFPV,RFLLDYDAL F,LQEKRFLLDY,KRFLLDYDAL,LDYDALFPVA ASCC3 c.3590G>A p.R1197Q VKQCVHQIPSVMMEASIQPITRTVL[p.RI197Q] TVLQVTLSI,VLQVTLSIY,LQVTLSIYA,VLQVTLSIYA,ITRTV CRC QVTLSIYADFTWNDQVHGTVGEPWWI LQVTL,RTVLQVTLSI,TVLQVTLSIY,QPITRTVLQV ASCC3 c.407G>A p.R136Q ETKAIKQMFGPFPSSSATAACNATN[p.R136Q] ATNQIISHF,TAACNATNQI,NATNQIISHF UCEC QIISHFSQDDLTALVQMTEKEHGDRV ASCL4 c.105de|C p.D35fs ALPYSLRTAPLGVPGTLPGLPRRDP[p.D35fs]S RAGSGRAAA,STCPCRWTA,WTAPSSPPS,TPRAGSGRA,AP STAD GSPCVWTPRAGSGRAAAAHGDGSTCPCRWTAPSS SSPPSSA,DPSGSPCVW,RAGSGRAAAA,RWTAPSSPPS,SG PPSSASATSASGSGCAA* SPCVWTPR,TPRAGSGRAA ASIC2 c.137G>T p.R46L RMAREEPAPAALAAAGQPGGGRGGE[p.R46L] ELALQGPGV,GELALQGPG,QPGGGRGGEL,GELQLQGPGV KIRP LALQGPGVARRGRPSLSRAKLHGLRH ASPDH c.797A>G p.Q266R AVHTRRENPAEPGAVTGSATVTAFW[p.Q266R] SATVTAFWR,TAFWRSLLA,RSLLACCQL,TVTAFWRSL, ACC RSLLACCQLPSRPGIHLC* VTAFWRSLL,GSATVTAFWR,ATVTAFWRSL, TVTAFWRSLL,VTAFWRSLLA,WRSLLACCQL ASPM c.719C>T p.S240F EENKIPISPISPAFNECHGATCLPL[p.S240F] ATCLPLFVR,HGATCLPLF,FVRRSTTYS,LFVRRSTTY, LUAD FVRRSTTYSSLHASENRELLNVHSAN TCLPLFVRR,LPLFVRRST,ATCLPLFVRR,LPLFVRRSTT, PLFVRRSTTY,CHGATCLPLF ASPN c.201de|T p.F67fs DDDDDDDDDEDNSLFPTREPRSHFF[p.F67fs] DVSAIHELY,SHFFHLICF,CFQCVHLDV,RSFHFFHLIC, STAD HLICFQCVHLDVSAIHELYIAQI* EPRSHFFHL,HLICFQCVH,LDVSAIHEL,HLICFQCVHL, HLDVSAIHEL,AIHELYIAQI,RSHFFFHLICF,DVSAIHELYI, EPRSHFFHLI,REPRSHFFHL,FQCVHLDVSA,LDVSAIHELY ASTN2 c.661_663 p.L221de| EIVEEQMHILHISVMGGLIALLLLL[p.L221de|] LIALLLLLV,ALLLLLVFT,IALLLLLVF,GLIALLLLLV, PRAD de|CTG VFTVALYAQRRWQKRRRIPQKSASTEAT ALLLLLVFTV,LIALLLLLVF ASXL2 c.3242C>T p.S1081L EGLSKATQDQILQTLIQRVRRQNLL[p.S1081L] RVRRQNLLL,LLVVPPSQF,RRQNLLLVV,RQNLLLVVP,RVRR LUSC LVVPPSQFNFAHSGFQLEDISTSQRF QNLLLV,LLLVVPPSQF,LVVPPSQFNF,RQNLLLVVPP ASXL3 c.2618de|A p.E873fs SIPELASTEMIKVKNHSVLQRTEKK[p.E873fs]C EMSFHLLNY,YLHHWNYLS,IIREMSFHL,YLSFLKGQI,LLNYR STAD YLHHWNYLSFLKGQIIREMSFHLLNYRTSNISHQW TSNI,HISKGVHRV,MSFHLLNYR,ALEIKHISK,HWNYLSFLK, IRLHFQKALEIKHISKGVHRVG* QWIRLHFQK,CYLHHWNYL,LHHWNYLSF,SHQWIRLHF,W IRLHFQKA,KCYLHHWNY,RTSNISHQW,SFLKGQIIR,SNISH QWIR,EIKHISKGV,GQIIREMSF,LQRTEKKCY,HHWNYLSFL, LSFLKGQII,LKGQIIREM,REMSFHLLN,IRLHFQKAL,LHFQK ALEI,FQKALEIKH,YLHHWNYLSF,HLLNYRTSNI,YLSFLKGQI I,FLKGQIIREM,QIIREMSFHL,IIREMSFFILL,RLFIFQKALEI,H QWIRLHFQK,KALEIKHISK,HHWNYLSFLK,LSFLKGQIIR,CY LHHWNYLS,NYLSFLKGQI,ISHQWIRLHF,KCYLHHWNYL,R TSNISHQWI,KKCYLHHWNY,REMSFHLLNY,EMSFHLLNYR, SNISHQWIR,MSFHLLNYRT,WIRLHFQKAL,LQRTEKKCYL, LHFIWNYLSFL,KGQIIREMSF,LNYRTSNISH,YRTSNISHQW, FQKALEIKHI,LEIKHISKGV,KHISKGVHRV,TEKKCYLHHW ASXL3 c.4409C>A p.P1470Q NRADNSGKPQQPPGGFAPAAINRSI[p.P1470Q]Q AINRSIQCK,RSIQCKVIV,AINRSIQCKV,AAINRSIQCK LUAD CKVIVDHSTTLTSSLSLTVSVESSE ATAD5 c.913A>G p.I305V EIPDSTMSICVPSETVDEIVKSGYI[p.I305V]GE YIGESENSEI TGCT SENSEISQQVRFKTVTVLAQVHPI ATM c.2399C>T p.S800F SLRNMMQLCTRCLSNCTKKSPNKIA[p.S800F]F KIAFGFFLR,AFGFFLRLL,SPNKIAFGF,KKSPNKIAF,NKIAFGF CESC GFFLRLLTSKLMNDIADICKSLASF FL,IAFGFFLRL,KIAFGFFLRL,KSPNKIAFGF,NKIAFGFFLR,SP NKIAFGFF,TKKSPNKIAF,IAFGFFLRLL ATP10B c.3910C>A p.L1304I CNSPTNPYWVMEGQLSNPTFYLVCF[p.L1304I] YLVCFITPV,LVCFITPVV,FITPVVALL,CFITPVVAL,YLVCFI UCEC ITPVVALLPRYFFLSLQGTCGKSLIS TPVV,FYLVCFITPV,CFITPWALL,ITPVVALLPR,NPTFYLVCFI ATP10 c.932G>A p.R311 AVVGIVVYAGHETKAMLNNSGPRYK[p. SGPRYKHSK,RYKHSKLER,GPRYKHSKL,NSGPRYKHSK CRC D H R311H]HSKLERRANTDVLWCVMLLVI MCLTG ATP12A c.2572C>T p.R858C LGTDIIPSIALAYEKAESDIMNRKP[p.R858C]C IMNRKPCHK,MNRKPCHKNK,DIMNRKPCHK BLCA HKNKDRLVNQPLAVYSYLHIGLMQA ATP2A1 c.2110G>T p.G704C VEPSHKSKIVEYLQSYDEITAMTGD[p.G704C]CV CVNDAPALK,ITAMTGDCV,AMTGDCVNDA,CVNDAPALK KIRC NDAPALKKAEIGIAMGSGTAVAKT K,EITAMTGDCV ATP2A1 c.2457_2458 p.R819 LVTDGLPATALGFNPPDLDIMDRPP[p.R819fs]PE HQWLALLPL,GSSCLVVPV,RGLCGCSHR,ALLPLHGNR,SSCL STAD insC fs PQGAPHQWLALLPLHGNRGLCGCSHRGSSCLVVPVR* VVPVR,APHQWLALL,LPLHGNRGL,CSHRGSSCL,EPQGAP HQW,LLPLHGNRGL,GSSCLVVPVR,CSHRGSSCLV,LALLPL HGNR,HQWLALLPLH,SHRGSSCLW,RGSSCLVVPV ATP2B4 c.548G>A p.R183H SVIIVVLVTAFNDWSKEKQFRGLQC[p.R183H]HIE KQFRGLQCH,CHIEQEQKF,KQFRGLQCHI CLL QEQKFSIIRNGQLIQLPVAEIVV ATP2C1 c.2170G>A p.E724K GTDVCKEAADMILVDDDFQTIMSAI[p.E724K]KE IMSAIKEGK,AIKEGKGIY,TIMSAIKEGK,SAIKEGKGIY,DFQTI UCEC GKGIYNNIKNFVRFQLSTSIAALT MSAIK,KEGKGIYNNI ATP6 c.355G>C p.E119Q ISYPLENAVPFSLDSVANSIHSLFS[p.E119Q] SLFSQETPV,FSQETPVVL,QETPVVLQL, HNSC AP2 QETPVVLQLAPSEERVYMVGKANSV SLFSQETPVV,HSLFSQETPV, LFSQETPVVL,SQETPVVLQL,QETPVVLQLA ATP6 c.572G>A p.R191Q MTGKLGFIAGVINRERMASFERLLW[p. SFERLLWQI,WQICRGNVY,FERLLWQIC,LL CRC V0A4 R191Q]QICRGNVYLKFSEMDAPLEDPV WQICRGNV,WQICRGNVYL,QICRGNV TKEE YLK,LWQICRGNVY,ASFERLLWQI ATP6 c.710T>C p.L237P RQVRPVTEKLPANHPLLTGQRVLDA[p.L237P]PF VLDAPFPCV,GQRVLDAPF,RVLDAPFPCV,TGQRVLDAPF THCA V1A PCVQGGTTAIPGAFGCGKTVISQS ATP6 c.1149de|C p.Y383 DLTGFITEGQIYVDRQLHNRQIYPP[p.Y383fs]STCS IYPPSTCSL,RQIYPPSTC,QIYPPSTCSL,RQIYPPSTCS STAD V1B1 fs LPCRG* ATP6 c.934_935 p.R312fs STFPDHKVKVTPLGNPDRPAAGQTD[p.R312fs]KE KERERVRAR,RERVRARVR,RVRARVRAP,RARVRAPCC,RV STAD V1C2 insAG RERVRARVRAPCCAGSR* RAPCCAG,RAPCCAGSR,RVRARVRAPC,RARVRAPCCA,RV RAPCCAGS,KERERVRARV,RERVRARVRA ATP7A c.2968_2969 p.Q990 IVETYFPGYNRSISRTETIIRFAFQ[p.Q990fs]SL HSNCCDGGY,FQSLYHSSV,SLYHSSVYC,LYHSSVYCM,IIRFA KIRC insA fs YHSSVYCMSLFTGTGHSNCCDGGYRSRCSKWHTNKRWR FQSL,RFAFQSLYH,GGYRSRCSK,RSRCSKWHT,RCSKWHT AIGDGS* NK,CSKWHTNKR,KWHTNKRWR,HTNKRWRAI,RWRAIGD GS,IRFAFQSLY,QSLYHSSVY,SSVYCMSLF,FAFQSLYHS,HSS VYCMSL,MSLFTGTGFI,SKWFITNKRW,SLYFISSVYCM,TIIR FAFQSL,HSNCCDGGYR,IIRFAFQSLY,RSRCSKWHTN,KWH TNKRWRA,HTNKRWRAIG,FQSLYHSSVY,HSSVYCMSLF,G HSNCCDGGY,ETIIRFAFQS,FAFQSLYHSS,YHSSVYCMSL,G GYRSRCSKW ATP9A c.1556G>A p.R519Q VYQASSPDEVALVQWTESVGLTLVG[p.R519Q]Q LVGQDQSSM,GQDQSSMQL,TLVGQDQSSM BLCA DQSSMQLRTPGDQILNFTILQIFPF ATP9A c.869G>A p.R290Q ASGTVVGVVLYTGRELRSVMNTSNP[p.R290Q]QS NTSNPQSKI,NPQSKIGLF,VMNTSNPQSK UCEC KIGLFDLEVNCLTKILFGALVVVS ATP9B c.115A>G p.S39G AAAAANRKRAAYYSAAGPRPGADRH[p.S39G]GR RPGADRHGRY ACC YQLEDESAHLDEMPLMMSEEGFEN ATR c.5440de|A p.R1814 NYLAADGKSTTWSVRLGQLLLSAKK[p.R1814fs]E AKKEISQLF,KKEISQLFM,KEISQLFMT,SAKKEISQLF,AKKEI UCEC fs ISQLFMTH* SQLFM,KEISQLFMTH ATRN c.590C>A p.P197Q LRFNHFATECSWDHLYVYDGDSIYA[p.P197Q]QL SIYAQLVAA,QLVAAFSGL,IYAQLVAAF,AQLVAAFSG,AQLV LUAD VAAFSGLIVPERDGNETVPEWAT AAFSGL,QLVAAFSGLI,SIYAQLVAAF,DSIYAQLVAA ATRNL1 c.3732A>T p.L1244F IAFSQHNTIMDLVQFFVTFFSCFLS[p.Ll244F] FSCFLSFLL,FLSFLLVAA,FFSCFLSFL,LSFLLVAAV,TFFSCFLSF, CLL FLLVAAVVWKIKQTCWASRRREQLLR FLLVAAVVW,FSCFLSFLLV,FFSCFLSFLL,FLSFLLVAAV,VTF FSCFLSF,TFFSCFLSFL,SFLLVAAVVW,LSFLLVAAVV ATRX c.5807A>G p.K1936R IASDSDETSMSLSSDDYTKKKKKGK[p.K1936R]RG YTKKKKKGKR TGCT KKDSSSSGSGSDNDVEVIKVWNSR ATXN1 c.651G>T p.Q217H GHKAEQQQQQQQQQQQQHQHQQQQQ[p.Q217H]H HQHQQQQQH,HQQQQQQQQH LIHC QQQQQQQQHLSRAPGLITPGSPPPA AURKA c.1160C>T p.S387L RLLKHNPSQRPMLREVLEHPWITAN[p.S387L]L HPWITANLS,LSKPSNCQNK,LEHPWITQNL CESC SKPSNCQNKESASKQS* AVIL c.190G>T p.G64W EGDCYVILSTRRVASLLSQDIHFWI[p.G64W] SQDIHFWIW,SQDIHFWIWK,LSQDIHFWIW LUAD WKDSSQDEQSCAAIYTTQLDDYLGGS SKPSNCQNKESASKQS* AVIL c.896_897 p.G299 DLLNHDDCYILDQSGTKIYVWKGKG[p.G299fs] VWKGKGSHK,YVWKGKGSHK KIRC insG fs SHKG* AVL9 c.102C>A p.F34L DGVPRGPVLHIVVVGFHHKKGCQVE[p.F34L]LSY KGCQVELSY,HKKGCQVEL,CQVELSYPP,VELSYPPLI,CQVEL UCEC PPLIPGDGHDSHTLPEEWKYLPF SYPPL,KKGCQVELSY AVL9 c.21_22insG p.G7fs MEKARRGG[p.G7fs]GWRPPGARTAHRGGRISPQE KARRGGGWR,RTAHRGGRI,RPPGARTAH,GRISPQEGL,KA ACC GLPG* RRGGGWRP,GWRPPGARTA,GARTAHRGGR,MEKARRGGGW AVPR1A c.1053de|T p.F351fs ENPTITITALLGSLNSCCNPWIYMF[p.F351fs]LV WIYMFLVAI,YMFLVAISF,FLVAISFKT,LVAISFKTV,TVFKAS STAD AISFKTVFKASHAAKT* HAA,MFLVAISFK,AISFKTVFK,IYMFLVAIS,KTVFKASHA,VF KASHAAK,VAISFKTVF,ISFKTVFKA,FKTVFKASH,NPWIYM FLV,FLVAISFKTV,AISFKTVFKA,YMFLVAISFK,VAISFKTVFK, TVFKASHAAK,PWIYMFLVAI,IYMFLVAISF,SFKTVFKASH, KTVFKASHAA,LVAISFKTVF,NPWIYMFLVA AVPR1B c.115G>A p.G39R RGTLSAPNATTPWLGRDEELAKVEI[p.G39R]R RVLATVLVL,ELAKVEIRV,EIRVLATVL,VEIRVLATV,RVLATVLVLA, TGCT VLATVLVLATGGNLAVLLTLGQLGR KVEIRVLATV,EIRVLATVLV,AKVEIRVLAT,VEIRVLAT VL,IRVLATVLVL,EELAKVEIRV AXDND1 c.2790G>T p.E930D WRESAKQGTLAQKYLEAMAVIEHMQ[p.E930D]DK HMQDKLLEV,AVIEHMQDK,IEHMQDKLL,AVIEHMQDKL CRC LLEVENRARQAEEKFEDAYEKLHH AXDND1 c.301T>C p.W101R CPENLLPPKKIKTPKGTLPRLVDHV[p.W101R]RH HVRHHPVRR,RHHPVRRNK,RLVDHVRHH,LVDHVRHHPV, LUAD HPVRRNKFKYLIDHPVSLTGAGRD HVRHHPVRRN,RHHPVRRNKF AXIN2 c.1988_199 p.W663fs QSTKKAYPLESARSSPGERASRHHL[p.W663fs]ST HLSTAGTPA,RASRHHLST,ASRHHLSTA,PTCSPRTLR,TPAPPPVPT, CRC 4de|GGGGGGG AGTPAPPPVPTCSPRTLRCLP* VPTCSPRTL,RASRHHLSTA,ASRHHLSTAG,HHLSTAGTPA AXIN2 c.1993_1994 p.G665fs KKAYPLESARSSPGERASRHHLWGG[p.G665fs]QQ HLWGGQQRA,GQQRAPPHH CRC insG RAPPHHPPCPPVHPGPCDASPDPTQHAGSAGGGLSQAS* AXIN2 c.1994de|G p.G665fs TKKAYPLESARSSPGERASRHHLWG[p.G665fs]AT HLWGATAGT,ASRHHLWGA,PTCSPRTLR,TPAPPPVPT,VP STAD AGTPAPPPVPTCSPRTLRCLP* TCSPRTL,RHHLWGATA,WGATAGTPA,RASRHHLWGA,ASRHHLWG AT,RHHLWGATAG B2M c.1A>G p.M1V [p.M1V]VSRSVALAVLALLSLSGLEAIQRTPK VSRSVALAV,VSRSVALAVL OV B2M c.37_38de|CT p.L13fs MSRSVALAVLALLS[p.L13fs]FWPGGYPAYSK LLSFWPGGY,LLCVWVSSI,LTSSSREWK,SSSREWKVK,KFPE CRC,STAD DSGLLTSSSREWKVKFPELLCVWVSSIRH* LLCVW,KVKFPELLC,FWPGGYPAY,TSSSREWKV,EWKVKF PEL,LAVLALLSF,SFWPGGYPA,LLTSSSREW,SSREWKVKF, WKVKFPELL,VKFPELLCV,REWKVKFPE,FPELLCVWV,ELLC VWVSSI,ALLSFWPGGY,LLTSSSREWK,TSSSREWKVK,SFW PGGYPAY,KFPELLCVWV,KVKFPELLCV,DSGLLTSSSR,LLCV WVSSIR,LSFWPGGYPA,LTSSSREWKV,YPAYSKDSGL,ALA VLALLSF,LAVLALLSFW,GLLTSSSREW,SSSREWKVKF,REW KVKFPEL,VKFPELLCVW B2M c.3G>A p.M1I [p.M1I]ISRSVALAVLALLSLSGLEAIQRTPK ISRSVALAV,ISRSVALAVL HNSC B3GALNT1 c.434G>A p.R145Q QEAEKEDKMLALSLEDEHLLYGDII[p.Rl45Q]Q IQQDFLDTY,LYGDIIQQDF,IIQQDFLDTY CRC QDFLDTYNNLTLKTIMAFRWVTEFC B3GAT1 c.374G>T p.R125L AELTRMANTLLHVPNLHWLVVEDAP[p.R125L]LRTP WLVVEDAPL,VEDAPLRTPL LUAD LTARLLRDTGLNYTHLHVETPR B3GNT5 c.88de|T p.F30fs GRRVKKWQLIIQLFATCFLASLMFF[p.F30fs]GNQ FLASLMFFG,LMFFGNQSI,MFFGNQSII,FGNQSIITL,FLASL STAD SIITL* MFFGN,SLMFFGNQSI,LMFFGNQSII,FFGNQSIITL B4GALNT1 c.263_264insG p.G88fs PVRIKEQVVGLLAWNNCSCESSGGG[p.G88fs]PPPP PLPETSPSY,PPLPETSPSY PRAD LPETSPSY* BACH1 c.1613G>A p.R538Q ESCSAREQECEVKLPFNAQRIISLS[p.R538Q]QN SQNDFQSLL,AQRIISLSQ,IISLSQNDF,LSQNDFQSL,SLSQN CRC DFQSLLKMHKLTPEQLDCIHDIRR DFQSL,SQNDFQSLLK,RIISLSQNDF,LSQNDFQSLL BAG1 c.133G>C p.G45R RLRALRPGREPRQSEPPAQRGPPPS[p.G45R]RR AQRGPPPSR,AQRGPPPSRR,GPPPSRRPPA ACC PPARSTASGHDRPTRGAAAGARRP BAI2 c.692C>G p.A231G EECGRAAGRACGFAQPGCSCPGEAG[p.A231G]G GEAGGGSTT,GEAGGGSTTT TGCT GSTTTTSPGPPAAHTLSNALVPGGP BAIAP2L2 c.1186G>A p.V396M SSASGWFPEAYVKALEEGPVNPMTP[p.V396M]M NPMTPMTPM,GPVNPMTPM,TPMTPMTSM,MTPMTPM KIRP TPMTSMTSMSPMTPMNPGNELPSRS TSM,MTPMTSMTSM,TPMTPMTSMT BAP1 c.233A>G p.N78S IEERRSRRKVSTLVDDTSVIDDDIV[p.N78S]SNM IVSNMFFAH,DIVSNMFFA,SNMFFAHQL,SNMFFAHQLI,V KIRC FFAHQLIPNSCATHALLSVLLNC SNMFFAHQL BAP1 c.679C>T p.R227C WTDKARRVIMERIGLATAGEPYHDI[p.R227C]CF PYHDICFNL,DICFNLMAV,YHDICFNLM,GEPYHDICF,HDIC OV NLMAVVPDRRIKYEARLHVLKVNR FNLMA,PYHDICFNLM,DICFNLMAW,EPYHDICFNL,HDICFNLMAV BARX2 c.203G>C p.R68P SLYSVCPSLVVRPKPLHSCTGSPSL[p.R68P]P TGSPSLPAY,LPAYPLLSV,SPSLPAYPL,CTGSPSLPAY,SLPAY LUAD AYPLLSVITRQPTVISHLVPATPGI PLLSV,SPSLPAYPLL,LPAYPLLSVI BAX c.114_115insG p.M38fs SEQIMKTGALLLQGFIQDRAGRMGG[p.M38fs]G RMGGGGTRA,GTRAGPGPG,RVSQAHRGR,QEAERVSQA, STAD GTRAGPGPGASGCVHQEAERVSQAHRGRTGQ* AGRMGGGGTR,GTRAGPGPGA,RMGGGGTRAG,HQEAER VSQA,QEAERVSQAH BBOX1 c.526T>G p.F176V RLTGASDKPGEVSKLGKRMGFLYLT[p.F176V]V RMGFLYLTV,TVYGHTWQV,YLTVYGHTW,MGFLYLTVY,FLYLT CRC YGHTWQVQDKIDANNVAYTTGKLSF VYGHT,LTVYGHTWQV,RMGFLYLTVY,LYLTVYGHTW,KRMGFLYLTV BBS9 c.802de|T p.F268fs ALDICIVSFNQSASSVFVLGERNFF[p.F268fs] VLGERNFFA,FALRIMDKF,RNFFALRIM,FVLGERNFFA,VLGERN PRAD ALRIMDKFDS* FFAL,NFFALRIMDK,FFALRIMDKF,GERNFFALRI,ERNFFALRIM BC139719 c.398T>G p.L133R SSKSRNAPRSSCGNCGARAPEHPPV[p.L133R]R PPVRRVESL,HPPVRRVESL,RRVESLNLPL PRAD RVESLNLPLLNGLREEGPGVFSRSV BCAS3 c.641C>T p.T214M DLHCNKRILVVVLQEKIAAFDSCTF[p.T214M]M CTFMKKFFV,AFDSCTFMK,TFMKKFFVT,AAFDSCTFM,FM BLCA KKFFVTSCYPCPGPNMNPIALGSRW KKFFVTS,MKKFFVTSC,FMKKFFVTSC,AAFDSCTFMK,AFD SCTFMKK,MKKFFVTSCY,IAAFDSCTFM,FDSCTFMKKF BCKDHA c.111de|C p.H37fs RGLSQAALLLLRQPGARGLARSHPP[p.H37fs]G SSSSFHLWM,RSHPPGSSS,HPPGSSSSF,SSQGPRRSL,GSSS STAD SSSSFHLWMTSPSSQGPRRSL* SFHLW,FHLWMTSPS,WMTSPSSQG,MTSPSSQGPR,RGLARSH PPG,RSHPPGSSSS,SHPPGSSSSF,GSSSSFHLWM,FHLWMTSPSS BCKDHA c.385_395de| p.G129fs LCCFWPVGIAAFCLAQKVSLCVGLG[p.G129fs]I SLCVGLGIK,CVGLGIKEK,KQRAIYLRR,IYLRREGGR,APQKQ PAAD GGGGAC KEKNAPQKQRAIYLRREGGR* RAIY,KVSLCVGLGI,VSLCVGLGIK,GIKEKNAPQK,KQRAIYLR TGGGC RE,AIYLRREGGR,APQKQRAIYL BCL11A c.1735G>A p.E579K SMQHFSEAFHQVLGEKHKRGHLAEA[p.E579K]KG HLAEAKGHR,AEAKGHRDT HNSC HRDTCDEDSVAGESDRIDDGTVNG BCL2 c.515A>G p.N172S IVAFFEFGGVMCVESVNREMSPLVD[p.N172S] LVDSIALWM,SIALWMTEY,EMSPLVDSI,MSPLVDSIA,SPL DLBCL SIALWMTEYLNRHLHTWIQDNGGWDA VDSIAL,REMSPLVDS,DSIALWMTEY,SIALWMTEYL,MSPL VDSIAL,REMSPLVDSI,SPLVDSIALW BCL2 c.6C>T>G p.H20Q MAHAGRTGYDNREIVMKYI[p.H20Q]QYKL VMKYIQYKL,IVMKYIQYK,YIQYKLSQR,IQYKLSQRG,REIVM DLBCL SQRGYEWDAGDVGAAPPGAAPA KYIQ,IVMKYIQYKL,EIVMKYIQYK,IQYKLSQRGY,KYIQYKLS QR,REIVMKYIQY BCL2 c.97G>A p.G33R GYDNREIVMKYIHYKLSQRGYEWDA[p.G33R]R YEWDARDVG,SQRGYEWDAR,YEWDARDVGA DLBCL DVGAAPPGAAPAPGIFSSQPGHTPH BCL2L11 c.272G>A p.R91Q PPASPGPFATRSPLFIFMRRSSLLS[p.R91Q]QS QSSSGYFSF,LLSQSSSGY,LSQSSSGYF,SQSSSGYFS,SQSSSG CRC SSGYFSFDTDRSPAPMSCDKSTQT YFSF,SLLSQSSSGY,LLSQSSSGYF,FMRRSSLLSQ BCL2L11 c.560_561 p.L187fs YARRVFLNNYQAAEDHPRMVILRLL[p.L187fs]T STAVSWCHY,TAVSWCHYY,ELDGTTFLF,LTLHCPPGV,AVS UCS insA LHCPPGVENALTGSLRSRDTMQTFCLFKP WCHYYA,SLVEGAGDV,MVILRLLTL,TMQTFCLFK,DTMQTFCLF,H TRPSTAVSWCHYYAASGSLVEGAGDVSEDT YYAASGSL,YYAASGSLV,LFITTQQNF,RSRDTMQTF, ELDGTTFLFITTQQNF* LFKPTRPST,VSWCHYYAA,TFCLFKPTR,CPPGVENAL,KPTR PSTAV,RMVILRLLT,VENALTGSL,GSLRSRDTM,TELDGTTF L,STAVSWCHYY,ELDGTTFLFI,RMVILRLLTL,LLTLHCPPGV, AVSWCHYYAA,FLFITTQQNF,DTMQTFCLFK,QTFCLFKPTR, HYYAASGSLV,TELDGTTFLF,RSRDTMQTFC,LFKPTRPSTA, PSTAVSWCHY,NALTGSLRSR,TAVSWCHYYQ,LRSRDTMQ TF,RDTMQTFCLF,MQTFCLFKPT,CHYYAASGSL BCL7A c.155C>T p.T52M KVRKWEKKWVTVGDTSLRIYKVVVPV[p.T52M]ME RIYKWVPVM,KWVPVMEPK,LRIYKWVPVM CRC PKVDDKNKNKKKGKDEKCGSEVTT BCL9L c.2938G>T p.G980C PQTPSQMVPLPSANPPGPLKSPQVL[p.G980C]CSSL QVLCSSLSV,SPQVLCSSL,QVLCSSLSVR LUAD SVRSPTGSPSRLKSPSMAVPSP BCL9L c.3379_3380 p.P1127fs YHNAIKTIATSDDELLPDRPLLPPP[p.P1127fs]T LLPPPTTTA,RARDQQQPA,LSRCPEPYG,ELSRCPEPY,TTTA STAD insC TTAGLRARDQQQPAQPDAPELSRCPEPYGH GLRAR,EPARPAAPV,RPLLPPPTTT,LPPPTTTAGL,QPAQPD EPARPAAPVP* APEL,YGHEPARPAA,HEPARPAAPV BCLAF1 c.109_110 p.R37fs RSKSRSQSSSRSRSRSHSRKKRYSS[p.R37fs]T LVVEIVCIL,CILEIIVAI,IIVAITEII,LVPEHIQGL,HIQGLV CRC insCA GLVPEHIQGLVVEIVCILEIIVAITEIIEE* VEI,GLVVEIVCI,EIVCILEII,EIIVAITEI,SRKKRYSST,KKRY SSTGL,KRYSSTGLV,VEIVCILEI,VPEHIQGLV,GLVPEHIQGL,LVP EHIQGLV,HIQGLVVEIV,GLVVEIVCIL,HSRKKRYSST,KKRYSSTGL V,EIVCILEIIV,EIIVAITEII,VPEHIQGLVV,RKKRYSSTGL,LEIIV AITEI,VEIVCILEII BCOR c.4376A>G p.N1459S LPCSSSPQETTQSRPMPPEARRLIV[p.N1459S]S EARRLIVSK,VSKNAGETL,SKNAGETLL LUAD KNAGETLLQRAARLGYEEVVLYCLE BEND2 c.1607C>A p.P536Q RILFSKEILISSSVDIHLKDSQSLD[p.P536Q]QN DQNKMAALR,SQSLDQNKM,SLDQNKMAAL LUAD KMAALREYLATTFPTCDLHEHGKD BEND2 c.1888G>A p.E630K NDQRGRDGGEGCSWMFQPMNNSKMR[p.E630K]K PMNNSKMRK,MNNSKMRKK,KMRKKRNLQ,SKMRKKRNL, MM KRNLQPNSNAIPEGMREPSTDNPEE KMRKKRNLQP,MNNSKMRKKR,NSKMRKKRNL BEND3 c.793de|G p.D265fs FQPPPEYQLTAAELKQIVDQSLSGG[p.D265fs]T SLSGGTWPA,TMWRSTTPR,GAAVPVALR,CSSSATMWR,T STAD WPAACWCSSSPSSSATWTSPGAAVPVALRPSASWSR SPGAAVPV,VPVALRPSA,RPSASWSRC,CTCSSSATM,DQSL CTCSSSATMWRSTTPR* SGGTW,VALRPSASW,WPAACWCSS,SLSGGTWPAA,ATW TSPGAAV,WTSPGAAVPV,ALRPSASWSR,ATMWRSTTPR, WSRCTCSSSA,SSATWTSPGA,SPGAAVPVAL,RPSASWSRC T,SSSPSSSATW,RCTCSSSATM,WPAACWCSSS BEND5 c.592C>T p.R198C LEDAVVPRALYEELLRNYQQQQEEM[p.R198C]CH QQQEEMCHL,YQQQQEEMCH,QQQQEEMCHL,EEMCHLQQEL CRC LQQELERTRRQLVQQAKKLKEYGA BEST3 c.1148C>T p.P383L SFLGSTVQMGKQMPKNEWKMEDIKI[p.P383L]LLP KMEDIKILL,WKMEDIKIL,KILLPQPQF,LLPQPQFQCA,WK TGCT QPQFQCAKSDPGG* MEDIKILL,IKILLPQPQF BEST3 c.1331_1332 p.P444fs SSMFLPRDDLSPARDLLDVPSRNPP[p.P444fs]QG HLEEILLPR,LPRRKPHAA,AALQHGRAV,FPHQNATGT,LQH STAD insC LTHLEEILLPRRKPHAALQHGRAVHHQGDQPDKH GRAVHH,CENFPFIQNA,LLPRRKPHAA,HLEEILLPRR,HAAL FTEPDPTVQCENFPHQNATGT* QHGRAV,VPSRNPPQGL,LPRRKPHAAL,AALQHGRAVH,LQ HGRAVHHQ,HQGDQPDKHF,KHFTEPDPTV,CENFPHQNAT BHLHE22 c.185T>A p.L62Q STPPGMDLSLAPPPRERPASSSSSP[p.L62Q]QG SPQGCFEPA,SSSSPQGCF,RPASSSSSPQ,SSSSSPQGCF ACC CFEPADPEGAGLLLPPPGGGGGGS BICD2 c.485G>A p.R162H SENERLASVAQELKEINQNVEIQRG[p.R162H]HL RGHLRDDIK,HLRDDIKEY,HLRDDIKEYK,NVEIQRGHLR,IQR CRC RDDIKEYKFREARLLQDYSELEEE GHLRDDI,GHLRDDIKEY BIRC6 c.1240G>C p.V414L SCFGSGSCPHFLAAATKRGKICIWD[p.V414L]LSK KICIWDLSK,CIWDLSKLMK,LSKLMKVHLK,ICIWDLSKLM TGCT LMKVHLKFEINAYDPAIVQQLIL BIRC8 c.673_674 p.A225M VFIPCGHLVTCKQCAEAVDRCPMCS[p.A225M]M MVIDFKQRV,MCSMVIDFK,VDRCPMCSM,PMCSMVIDF,S TGCT GC>AT VIDFKQRVFMS* MVIDFKQRV,PMCSMVIDFK,CSMVIDFKQR,CPMCSMVID F,MVIDFKQRVF BLM c.1980T>A p.H660Q ASRNLKHERFQSLSFPHTKEMMKIF[p.H660Q]Q KIFQKKFGL,EMMKIFQKK,KEMMKIFQK,MMKIFQKKF,FQ KIRC KKFGLHNFRTNQLEAINAALLGEDC KKFGLHN,QKKFGLHNF,KIFQKKFGLH,EMMKIFQKKF,FQK KFGLHNF,KEMMKIFQKK,MMKIFQKKFG,MKIFQKKFGL BLVRA c.131C>T p.S44L AGSVRMRDLRNPHPSSAFLNLIGFV[p.S44L]LR FLNLIGFVL,VLRRELGSI,NLIGFVLRR,IGFVLRREL,FVLRREL CRC RELGSIDGVQQISLEDALSSQEVE GSI,AFLNLIGFVL,FLNLIGFVLR BMP2K c.1461C>G p.H487Q QQQQQQQQQQQQQQQQQQQQQQQQQ[p.H487Q]QH QQHHHHHHHL,QHHHHHHHLL TGCT HHHHHHLLQDAYMQQYQHATQQQQ BMP3 c.1030C>T p.R344W KPYKTLQAQAPEKSKNKKKQRKGPH[p.R344W]WK HWKSQTLQF,KQRKGPHWK,GPHWKSQTL,KKQRKGPHW, CRC SQTLQFDEQTLKKARRKQWIEPRN KKQRKGPHWK,KQRKGPHWKS,KKKQRKGPHW,PHWKSQTLQF BMP6 c.353A>T p.Q118L PRPLHGLQQPQPPALRQQEEQQQQQ[p.Q118L]L QEEQQQQQL,QQEEQQQQQL,QEEQQQQQLL KIRP LPRGEPPPGRLKSAPLFMLDLYNAL BMPER c.1329_1340 p.RIAL4 KSVELVLGESRVSLQQHLTVRWNGS[p.RIAL444de|] RWNGSPCRA,TVRWNGSPCR,NGSPCRAPHF,SPCRAPHFHI KIRC de|GCGCA 44de| PCRAPHFHIDLDGYLLKVTTKAGLEISWDGDSFVEVM TCGCGCT BMPER c.722G>A p.R241 PPGQCCPKCLGQRKVFDLPFGSCLF[p.R SCLFQSDVY,GSCLFQSDVY,LPFGSCLFQS UCEC Q 241Q]QSDVYDNGSSFLYDNCTACTCR DSTV BMS1 c.1364G>T p.G455V KAIFGDEDESGDSDDEEDDEMSEDD[p.G455V]VLE DEMSEDDVL LUAD NGSSDEEAEEEENAEMTDQYMAV BMS1 c.2634G>T p.E878D GEMQKQAQLNRAEFEDQDDEARVQY[p.E878D]DG YDGFRPGMY,DGFRPGMYV,VQYDGFRPG,QYDGFRPGM KIRP FRPGMYVRIEIENVPCEFVQNFDP Y,EARVQYDGFR,DGFRPGMYVR,VQYDGFRPGM,DEARVQYDGF BNC1 c.2809T>A p.Y937 MEKADQSLASLPSGLPITCHLCQKT[p.Y KTNSNKGTF,TNSNKGTFR,HLCQKTNSNK,KTNSNKGTFR, CLL N 937N]NSNKGTFRAHYKTVHLRQLHKC QKTNSNKGTF KVPG BNC2 c.1534C>T p.R512 NRHSANPNPRLHMPMLRNNRDKDLI LIWATSGAA,DLIWATSGA,DLIWATSGAA,WATSGAATPV CRC W [p.R512W]WATSGAATPVIASTKSNLAL TSPGRP BNC2 c.1723A>C p.S575 LQNPLPSQLVFSGLKTVQPVPPFYR[p.S RLLTPGEMV,QPVPPFYRR,VPPFYRRLL,RRLLTPGEM,QPV STAD R 575R]RLLTPGEMVSPPTSLPTSPIIPTSG PPFYRRL,YRRLLTPGEM T BPI c.765G>T p.M25 IDSVAGINYGLVAPPATTAETLDVQ[p. LDVQIKGEF,TTAETLDVQI,LDVQIKGEFY BLCA 5I M255I]IKGEFYSENHHNPPPFAPPVME FPAA BRAF c.1208de|C p.P403f NIDDLIRDQGFRGDGGSTTGLSATP[p.P LSATPLPHY,SATPLPHYL,GLSATPLPH,TPLPHYLAH,GLSAT STAD s 403fs]LPHYLAH* PLPHY,STTGLSATPL,LSATPLPHYL BRAF c.1397G>T p.G466 LGRRDSSDDWEIPDGQITVGQRIGS[p. SVSFGTVYK,GSVSFGTVY,GQRIGSVSF,RIGSVSFGTV,GSVS LUAD V G466V]VSFGTVYKGKWHGDVAVKML FGTVYK,VSFGTVYKGK,IGSVSFGTVY,ITVGQRIGSV,VGQRI NVTAPT GSVSF BRAF c.1406G>C p.G469 RDSSDDWEIPDGQITVGQRIGSGSF[p. GSGSFATVY,SGSFATVYK,SFATVYKGK,FATVYKGKW,RIGS MM,PRAD A G469A]ATVYKGKWHGDVAVKMLNVT GSFATV,GSGSFATVYK,GSFATVYKGK,SFATVYKGKW,GQR APTPQQ IGSGSFA,GSGSFATVY BRAF c.1406G>T p.G469 RDSSDDWEIPDGQITVGQRIGSGSF[p. SGSFVTVYK,SFVTVYKGK,GSGSFVTVY,RIGSGSFVTV,GSG LUAD V G469V]VTVYKGKWHGDVAVKMLNVT SFVTVYK,GSFVTVYKGK,SFVTVYKGKW,GQRIGSGSFV,IGS APTPQQ GSFVTVY BRAF c.1798_179 p.V600 RDLKSNNIFLHEDLTVKIGDFGLAT[p.V6 ATKKSRWSG,KKSRWSGSH,ATKKSRWSGS,DFGLATKKSR, SKCM 9GT>AA K 00K]KKSRWSGSHQFEQLSGSILWMAP FGLATKKSRW EVIR BRAF c.1799T>A p.V600 RDLKSNNIFLHEDLTVKIGDFGLAT[p.V6 DFGLATEKSR,FGLATEKSRW CRC,GBM,LUAD, E 00E]EKSRWSGSHQFEQLSGSILWMAP MM,SKCM,THCA EVI BRAF c.1801A>G p.K601 DLKSNNIFLHEDLTVKIGDFGLATV[p.K6 VESRWSGSH,DFGLATVESR,ESRWSGSHQF,FGLATVESR DLBCL, E 01E]ESRWSGSHQFEQLSGSILWMAPE W SKCM VIR BRAF c.1803A>T p.K601 DLKSNNIFLHEDLTVKIGDFGLATV[p.K6 GLATVNSRW,DFGLATVNSR,NSRWSGSHQF,FGLATVNSR CLL N 01N]NSRWSGSHQFEQLSGSILWMAPE W VIR BRD3 c.70_71ins p.P24fs MSTATTVAPAGIPATPGPVNPPPP[p.P RGRNQIEPA,ETPVRLALL,RPQDQPAAV,LPARGRNQI,AEC STAD C 24fs]GGLQPQQARPQDQPAAVHAECG GGEDAL,LETPVRLAL,GEDALETPV,LLPARGRNQI,PVRLAL GEDALETPVRLALLPARGRNQIEPAGLS* LPAR,RLALLPARGR,TPVRLALLPA,QQARPQDQPA,ALETP VRLAL,LETPVRLALL BRD9 c.988G>T p.G330 HAADEARDRINRFLPGGKMGYLKRN[p. RNWDGSLLY,KMGYLKRNW,LKRNWDGSL,KRNWDGSLL, LUAD W G330W]WDGSLLYSVVNTAEPDADEE WDGSLLYSV,YLKRNWDGSL,KRNWDGSLLY,GKMGYLKRN ETHPVD W,LKRNWDGSLL,WDGSLLYSVV BRF1 c.1405G>T p.V469 DGELDLSGIDDLEIDRYILNESEAR[p.V4 ILNESEARL,RLKAELWMR,SEARLKAEL,ARLKAELWM,NES LUAD L 69L]LKAELWMRENAEYLREQREKEARI EARLKA,YILNESEARL,ILNESEARLK,SEARLKAELW AK BRK1 c.208A>C p.K70Q SRLATLNEKLTALERRIEYIEARVT[p.K70 ARVTQGETL,EARVTQGET KIRC Q]QGETLT* BRMS c.321de|G p.G107 LSQLRLRLEEVGAERAPEYTEPLGG[p.G WQGSTRASV,SGASRFAFR,ASRFAFRWQ,AFRWQGSTR,G STAD 1 fs 107fs]CSGASRFAFRWQGSTRASVWM GCSGASRF,CSGASRFAF,FAFRWQGST,FRWQGSTRA,GAS * RFAFRW,CSGASRFAFR,FAFRWQGSTR,ASRFAFRWQG,RF AFRWQGST,AFRWQGSTRA,RWQGSTRASV,LGGCSGASR F,GCSGASRFAF,SGASRFAFRW,FRWQGSTRAS,WQGSTR ASVW BRPF1 c.196C>T p.R66C HLYHYDHDNPPPPQQTPLRKHKKKG[p. GCQSRPANK,KHKKKGCQSR,KGCQSRPANK CRC R66C]CQSRPANKQSPSPSEVSQSPGRE VMS BRWD c.3956A>G p.K131 TSSGRRRVHDGKKSIRATNYVESNW[p. NYVESNWRK,ATNYVESNWR,RKQCKELVNL TGCT 1 9R K1319R]RKQCKELVNLIFQCEDSEPFRQ PVDL BRWD c.2359C>T p.R787 TVEKKKKPSYTTQRNDYEPSCGRSL[p.R RSLCRTQRK,CGRSLCRTQR,RSLCRTQRKR CRC 3 C 787C]CRTQRKRQHTYQTRSNIEHNSQ ASCQ BRWD c.478C>A p.H160 VNYVKPPNVVNITSARQLTGCSRFG[p. CSRFGNIFP,RFGNIFPSS,GNIFPSSAY,GCSRFGNIF,SRFGNI LUAD 3 N H160N]NIFPSSAYQHIKMHKRILGHLSS FPS,CSRFGNIFPS,RFGNIFPSSA,FGNIFPSSAY,TGCSRFGNI VYC F BST1 c.107G>C p.G36A LLQLLLQLLLLLLLLAAGGARARWR[p.G RARWRAEGT,RWRAEGTSA,WRAEGTSAH,RAEGTSAHL,G KIRP 36A]AEGTSAHLRDIFLGRCAEYRALLSPE ARARWRAEG,RARWRAEGTS,RWRAEGTSAH,ARWRAEG TSA,WRAEGTSAHL BTBD c.1352de|C p.T451f LSDLVSRAMHHLQPLNAKHHGNGTP[p. CTAHKWNGK,KTPTWSLPK,FAISCTAHK,KWNGKTPTW,R STAD 11 s T451fs]CTTSRGHCTGSPRPCTPFAISC GHCTGSPR,TSRWKGPSS,WSLPKSTSR,SPRPCTPFA,NGKT TAHKWNGKTPTWSLPKSTSRWKGPSS PTWSL,KHHGNGTPC,GSPRPCTPF,HKWNGKTPT,TPFAISC CCRR* TA,SLPKSTSRWK,RWKGPSSCCR,TWSLPKSTSR,CTPFAISC TA,SPRPCTPFAI,AKHHGNGTPC,TGSPRPCTPF,FAISCTAH KW,HKWNGKTPTW,WSLPKSTSRW,TPFAISCTAH BTBD c.1682C>T p.A561 LLPGVDCEPRQLRADDCFCASRKLD[p. KLDVVAIEA,VVAIEAKFK,ASRKLDVVA,KLDVVAIEAK,ASRK STAD 11 V A561V]VVAIEAKFKQDLGFRMLNCGRT LDVVAI,DVVAIEAKFK,RKLDVVAIEA,LDVVAIEAKF DLVK BTBD c.794G>C p.G265 CMESLFRDIYSRVVASGVPRSCSGP[p.G VPRSCSGPA,VPRSCSGPAS ACC 11 A 265A]ASGSGSGPGPSSGPGAAPAADK EREA BTBD c.1307C>T p.S436 HPYGSKWVHRQALHFLCEEFSQVMT[p. MTLDVFYEL,QVMTLDVFY,SQVMTLDVF,EEFSQVMTL,V CRC 7 L S436L]LDVFYELSKDHLLTAIQSDYLQA MTLDVFYEL,TLDVFYELSK,FSQVMTLDVF,SQVMTLDVFY, SEQ MTLDVFYELS,CEEFSQVMTL BTG1 c.91C>T p.L31F TRAATMIGEIAAAVSFISKFLRTKG[p.L3 RTKGFTSER,FLRTKGFTS,SKFLRTKGF,KGFTSERQL,FLRTK DLBCL 1F]FTSERQLQTFSQSLQELLAEHYKHH GFTSE,FTSERQLQTF,ISKFLRTKGF W BTLA c.256C>A p.Q86K KYCANRPHVTWCKLNGTTCVKLEDR[p. KLEDRKTSW,KLEDRKTSWK,TTCVKLEDRK,VKLEDRKTSW CLL Q86K]KTSWKEEKNISFFILHFEPVLPND NG BTN2 c.43C>T p.L15F MEPAAALHFSLPAS[p.L15F]FLLLLLLLL FSLPASFLL,SLPASFLLL,SFLLLLLLL,LPASFLLLL, TGCT A2 LSLCALVSAQFTVVGPA LHFSLPASF,ASFLLLLLL,FSLPASFLLL,SLPASFLLLL, HFSLPASFLL,SFLLLLLLLL,ALHFSLPASF,LPASFLLLLL, LHFSLPASFL,ASFLLLLLLL BTN3 c.457G>A p.E153 FQDGDFYEKALVELKVAALGSNLHV[p. ALGSNLHVK,GSNLHVKVK,NLHVKVKGY,ALGSNLHVKV,A UCEC A2 K E153K]KVKGYEDGGIHLECRSTGWYPQ ALGSNLHVK PQIQ BTRC c.1248T>G p.I416 FNNGMMVTCSKDRSIAVWDMASPTD MASPTDMTL,WDMASPTDM,MASPTDMTLR,MTLRRVLV KIRC M [p.I416M]MTLRRVLVGHRAAVNVVDF GH,DMASPTDMTL,SPTDMTLRRV DDKYIVS BTRC c.778G>T p.G260 TDSLWRGLAERRGWGQYLFKNKPPD[p. KNKPPDWNA,WNAPPNSFY,YLFKNKPPDW,DWNAPPNS LUAD W G260W]WNAPPNSFYRALYPKIIQDIE FY,WNAPPNSFYR TIESN BUB1 c.2988C>A p.F996 VFWDGSFWKLSQNISELKDGELWNK[p. KLFVRILNA,LWNKLFVRI,ELWNKLFVR,GELWNKLFV CRC B L F996L]LFVRILNANDEATVSVLGELAAE MNG BZRAP c.4248_4249 p.P141 CLEDMPGLVGGSSRRRGGGSPEKPP[p. SQQQWAPGL,HTGEGWPPR,QQQWAPGLW,QWAPGLW STAD 1 insA 6fs P1416fs]KPQAASRSPRTLQPTSQQQW TT,ASRSPRTLQ,AASRSPRTL,LQPTSQQQW,QQWAPGLW APGLWTTGPHTGEGWPPRN* T,SQQQWAPGLW,ASRSPRTLQP,TLQPTSQQQW,QQWA PGLWTT BZRAP c.4879G>A p.V162 VLRPSTAELVPARSPSETLAYQHLP[p.V TLAYQHLPI,HLPIRIFVA,AYQHLPIRI,LAYQHLPIR,LPIRIFVA CRC 1 7I 1627I]IRIFVALFDYDPVSMSPNPDAGE L,YQHLPIRIF,YQHLPIRIFV,HLPIRIFVAL,AYQHLPIRIF, EEL IRIFVALFDY,TLAYQHLPIR,ETLAYQHLPI,LPIRIFVALF, LAVQHLPIRI C10or c.253G>T p.A85S GRRRRSCSPAPTWPPLCCYPQSRPT[p. QSRPTSSAA,YPQSRPTSS,YPQSRPTSSA,SSAAGPGACM ACC f95 A85S]SSAAGPGACMRASGRPHGNTTA STAP C11or c.3331C>T p.R1111C KQTASQVEQPIITQGSSVTKITFEG[p.R1111C] FEGCQPPTV CRC f30 CQPPTVTKITGGSSVPKLTSPVTSIS C11or c.403G>T p.V135 PGSPNSEPVGWIAVYGQGYSPNSGD[p. GDLQGLQAA,SPNSGDLQGL,GDLQGLQAAW LUAD f68 L V135L]LQGLQAAWEALQTSGRPITPG TLRQL C11or c.782_783 p.S261f QLLQQHGAELPTHPSKKRKHSESPP[p.S SALPGPWFL,ALPGPWFLA,FLASQHCPC,ALAPARCPL,TLA STAD f9 insC s 261fs]QHPQCPDAEWNDQTGAWDRD SPGSAL,ASAPHSSPI,ATLASPGSA,HSSPIATLA,APHSSPIAT, SPASAPHSSPIATLASPGSALPGPWFLA AEWNDQTGA,RDSPASAPH,GSALPGPWF,HPQCPDAEW, SQHCPCPDTALAPARCPLPRPPAGQ* LPGPWFLAS,CPDTALAPA,ASAPHSSPIA,ATLASPGSAL,SA LPGPWFLA,LAPARCPLPR,APHSSPIATL,TALAPARCPL,RK HSESPPQH,AEWNDQTGAW,SQHCPCPDTA,SPIATLASPG, SPGSALPGPW C12or c.179A>T p.D60V LPITHTRQVPSKPIDHSTITSWVSP[p.D6 TITSWVSPV,WVSPVFDTA,ITSWVSPVF,SPVFDTAAG,STIT TGCT f32 OV]VFDTAAGSLFPAYQKHQNRARHSS SWVSPV,WVSPVFDTAA,VFDTAAGSLF,TITSWVSPVF RK C12or c.1004G>A p.R335 KLHRLQTALSLYSTSLCGLVLLVDN[p.R3 LVDNQINSY,NQINSYSGI,QINSYSGIK,GLVLLVDNQI,LLVD UCEC f4 Q 35Q]QINSYSGIKRDFATVCQECTDFHF NQINSY,QINSYSGIKR PR C12or c.82G>C p.E28Q APSGTVSDSESSNSSSDAEELERCR[p.E RCRQAAMPA,QAAMPAWGL,LERCRQAAM,CRQAAMPA CESC f43 28Q]QAAMPAWGLEQRPHVAGKPRA W,RQAAMPAWG,EELERCRQA,RQAAMPAWGL,ELERCR GAANS QAAM,RCRQAAMPAW,EELERCRQAA,AEELERCRQA C12or c.428A>C p.K143 VFYNGENSPVHKEKREAAKKKQERK[p. KQERKTRAK,KTRAKETLE,RKTRAKETL,KTRAKETLEK,ERKT TGCT f65 T K143T]TRAKETLEKKKLLKELWESSKKVH* RAKETL C13or c.200de|G p.R67fs QPGAFQLSGDQLVVARPGEPAAARG[p. STASAATSR,STGSSTASA,ASAATSRGM,SAATSRGMW,GE STAD f33 R67fs]ASTSSVTASCASTGSSTASAATS PAAARGA,SSTASAATSR,AARGASTSSV,STSSVTASCA,EPA RGMWN* AARGAST,RGASTSSVTA,TASAATSRGM,ASAATSRGMW C14or c.883G>A p.E295 FSLAKSEIGSSMSEILLSQVTNMRT[p.E2 KLSFNIQAL,RTKLSFNIQ,TNMRTKLSF,KLSFNIQALA,NMR CRC fl0l K 95K]KLSFNIQALAVCANICLATKDRQNPS TKLSFNI,LSQVTNMRTK,RTKLSFNIQA,SQVTNMRTKL,VT NMRTKLSF,KLSFNIQAL C14or c.268de|A p.R90fs SSDESDTNKKLKQTSRKKKKEKKKK[p.R NLPEALEAV,IMLQLILDI,MLQLILDIA,ILDIALFGL,RIKEIML STAD fl02 90fs]GSISIIRKQRGSMGRRVAAGLRQT QL,GLRQTPILK,ALFGLRTFR,KGSISIIRK,IALFGLRTF,LFGLR PILKRTNLPEALEAVKRNLRNRIKEIMLQ TFRL,IIRKQRGSM,KQRGSMGRR,RGSMGRRVA,GSMGRR LILDIALFGLRTFRL* VAA,MGRRVAAGL,AVKRNLRNR,KRNLRNRIK,RNRIKEIML, SISIIRKQR,TPILKRTNL,SMGRRVAAG,NLRNRIKEI,QLILDI ALF,KKKKGSISI,KKKGSISII,KRTNLPEAL,LRNRIKEIM,KEIM LQLIL,LQLILDIAL,SMGRRVAAGL,IMLQLILDIA,MLQLILDIA L,LILDIALFGL,ALFGLRTFRL,ILKRTNLPEA,RIKEIMLQLI,AG LRQTPILK,IALFGLRTFR,KQRGSMGRRV,RGSMGRRVAA, MGRRVAAGLR,GLRQTPILKR,RTNLPEALEA,AVKRNLRNRI, EAVKRNLRNR,EIMLQLILDI,SIIRKQRGSM,NLRNRIKEIM,L QLILDIALF,DIALFGLRTF,KKKKGSISII,RRVAAGLRQT,VAAG LRQTPI,LKRTNLPEAL,IKEIMLQLIL C14or c.343G>A p.D115 RKHQHHKKTKRKHGPSSSSRSETDT[p. RSETDTNSEK CRC fl02 N D115N]NSEKDKPSRGVGGSKKESEEPN QGNN C14or c.299G>T p.R100I ASRDMYFDIPLEHRETSIIKRHPPQ[p.Rl IIKRHPPQI,IKRHPPQIL,SIIKRHPPQI,IIKRHPPQIL,KRHPPQ CRC fl05 00I]ILQKLEPIDLPRVITSGRLLSQREAR ILQK C14or c.836G>T p.R279I GECVPGFTVPNLLPKWAPDHCSEVE[p. EIMDSGLDK,IMDSGLDKF,EIMDSGLDKF,SEVEIMDSGL UCEC fll8 R279I]IMDSGLDKFSDSTFLLPSRPAQR GYH C14or c.16C>T p.R6W MAEGS[p.R6W]WIPQARALLQQCLHA EGSWIPQAR,SWIPQARAL,QEGSWIPQA,SWIPQARALL,G KIRP fl26 RLQIRPADGDV SWIPARAL C14or c.690C>A p.F230 DSAALLCQALSTNYQIKKLDLSHNQ[p.F KLDLSHNQL,QLSDVGGEHL,KKLDLSHNQL UCEC fl66B L 230L]LSDVGGEHLGQMLAINVGLTSLD LSW C14or c.269G>T p.G90V CCGECSTCFCTEEKSECQRHEETSP[p.G SPVSCNHQI,CQRHEETSPV,SPVSCNHQIM CLL fl77 90V]VSCNHQIMSASTISAFCATPRFKQLF C14or c.939de|C p.P313f GLQPAGPLGQSHLAHHSMAPYPFPP[p. PYPFPPTQI,MAPYPFPPT,SMAPYPFPPT,APYPFPPTQI STAD f43 s P313fs]TQI* C15or c.1462G>A p.V488I LALPADLVPILGDQSNEKGGSYNSV[p.V NSVIGAAPL,KGGSYNSVI,GSYNSVIGAA,YNSVIGAAPL CRC f2 488I]IGAAPLTSDPPTPPSSTPSFKPPVTR C15or c.2257G>T p.V753 PGSGNTQPSGNTASVQGSTSLPAQS[p. SLPAQSFRA,TSLPAQSFR,QSFRAPATA,LPAQSFRAP,STSLP LUAD f2 F V753F]FRAPATASNHPLNPGATPQPKF AQSF,AQSFRAPAT,STSLPAQSFR,SFRAPATASN,LPAQSFR GAPD APA,GSTSLPAQSF,AQSFRAPATA C15or c.2716G>T p.G906 RRPTTTSSHPLNTGSISHSTLGATD[p.G WQQKSDSSF,LGATDWQQK,WQQKSDSSFI LUAD f2 W 906W]WQQKSDSSFILGNPATPAPVIGL TSP C15or c.71C>T p.S24F MAAPEAPPLDRVFRTTWLSTECD[p.S2 TWLSTECDF,DFHPLPPSY,STECDFHPL,DFHPLPPSYR,LSTE SKCM f23 4F]FHPLPPSYRKFLFETQAADLAGGTTV CDFHPL,CDFHPLPPSY C15or c.1018G>A p.D340 GSKKAPAKSVKERIADSQEHISTSI[p.D3 SINFNIIKI,TSINFNIIK,ISTSINFNI,STSINFNII,EHIST CRC f33 N 40N]NFNIIKILNNPRAYTLPISKEESRLS SINF,INFNIIKIL,HISTSINFNI,STSINFNIIK, TSINFNIIKI,QEHISTSINF,ISTSINFNII C15or c.294de|G p.G98fs RKKNQALLRRYQEIQEDRRQAEQGG[p. RQAEQGGWL STAD f52 G98fs]WL* C16or c.193G>A p.G65S RACPVACPVGCPIACPVSCPVACPV[p. VACPVSCPV,PVACPVSCPV,CPVSCPVGSM CESC f3 G65S]SCPVGSMATAPQGLSPQEWEA DRETG C16or c.353A>C p.D118 RASNETLVSCSSSGSDQQRTIREPE[p.D REPEAWGPY,RTIREPEAW,EAWGPYRRHR,IREPEAWGPY KIRC f55 A 118A]AWGPYRRHRNPSTADAYNSHLK E* C16or c.730C>A p.L244I SDTSVIQFYPSKFVLITDILDTFGK[p.L24 IVYERIFSM,TFGKIVYER,DILDTFGKI,LDTFGKIVY, TGCT f62 4I]IVYERIFSMCVDSRSVLPDHFSPENA GKIVYERIF,ILDTFGKIVY,TFGKIVYERI,KIVYERIFSM, DTFGKIVYER,FGKIVYERIF C16or c.61_63de| p.S21de| MGLKMSCLKGFQMCVSSSSS[p.S21de|] MCVSSSSSH,QMCVSSSSSH PRAD f74 AGC HDEAPVLNDKHLDVPDIIITPPTPTGMM C16or c.452G>T p.R151I ANLSDEKAFVFSVALAEINRKIINQ[o.Rl KIINQILIL,NRKIINQIL,RKIINQILI,EINRKIINQI, CRC f87 51I]ILIL* RKIINQILIL C17or c.187C>G p.L63V LCLRALAFCALAKPRASSLGPGPGE[p.L SLGPGPGEV,VAARSPVLR,EVAARSPVL,GEVAARSPV,EVA ACC f96 63V]VAARSPVLRGPQAPLRPGGWAPD ARSPVLR,GEVAARSPVL GLK C19or c.34G>C p.G12R MAAPSGGWNGV[p.G12R]RASLWAA GVRASLWAA,RASLWAALL,VRASLWAAL,GVRASLWAAL, ACC f10 LLLGAVALRPAEAVSEPTT GWNGVRASLW,RASLWAALLL,GGWNGVRASL,VRASLW AALL C19or c.784C>T p.R262 PHLANGHVVPIKPQVKGVVREENKV[p. CAVPTWASV,REENKVCAV,NKVCAVPTW,EENKVCAVPT STAD f21 C R262C]CAVPTWASVQVVDDPGSLASVESPGT C19or c.150de|C p.P50fs YDQELLGPSDKSQAALQKAGEVVPP[p. CVSRQACRY,LQRFTFPSV,SSASTCVSR,SQPLQRFTF,TFPSV STAD f70 P50fs]PCTSSASTCVSRQACRYPSSQPL TPGM,RQACRYPSS,CTSSASTCV,FTFPSVTPG,VPPPCTSSA, QRFTFPSVTPGMQAS* CRYPSSQPL,GEVVPPPCT,PLQRFTFPSV,FTFPSVTPGM,TS SASTCVSR,STCVSRQACR,SSQPLQRFTF,YPSSQPLQRF,FPS VTPGMQA,RQACRYPSSQ,LQRFTFPSVT C1QB c.674C>T p.T225I ESDIFSIREVSFQSTGESEWKDTNV[p.T2 NYILNTDSL,SEWKDTNYI,ILNTDSLDW,ILNTDSLDWA,SE TGCT P 25I]ILNTDSLDWALYDHLMDFLADRGV WKDTNYIL,YILNTDSLDW DN C1QT c.582_583 p.G194 CVWHIQVATDHAIQLKIEALSIESV[p.G ALSIESVGL,IESVGLLPF,LSIESVGLL,ALSIESVGLL, STAD NF5 insG fs 194fs]GLLPF* EALSIESVGL,SIESVGLLPF C1QT c.924de|C p.P308f NCADGSDETNCSAKFSGSVEQSHPP[p. QSHPPPRLLA,VEQSHPPPRL STAD NF5 s P308fs]PRLLAP* C1R c.647de|C p.P216f AECSSELYTEASGYISSLEYPRSYP[p.P21 TSSSWSLLI,ILMTTSKYT,SMPTGRTLA,QMSRGTAGA,LLIL STAD s 6fs]LTCAATTASGWSGASPCTSSSWSLL MTTSK,TLASSVGSK,YTAPMTSYR,RSSSAPSPR,RSYPLTCA ILMTTSKYTAPMTSYRSMPTGRTLASSV A,TTSKYTAPM,MTSYRSMPT,SYRSMPTGR,RSMPTGRTL, GSKGPPTSTPAAMLWICCSSQMSRGT RTLASSVGS,SSQMSRGTA,AGSCATPPR,ATPPRSSSA,LILM AGAGSCATPPRSSSAPSPRP* TTSKY,KYTAPMTSY,TTASGWSGA,CTSSSWSLL,STPAAML WI,YPRSYPLTC,APMTSYRSM,MPTGRTLAS,LEYPRSYPL,C AATTASGW,SSSWSLLIL,SSWSLLILM,LMTTSKYTA,SKYTA PMTS,LWICCSSQM,SQMSRGTAG,YPLTCAATT,PPTSTPA AM,TSTPAAMLW,TPAAMLWIC,CTSSSWSLLI,SLEYPRSYP L,ILMTTSKYTA,MLWICCSSQM,SQMSRGTAGA,SLLILMTT SK,RTLASSVGSK,TSYRSMPTGR,RSYPLTCAAT,MTTSKYTA PM,KYTAPMTSYR,RSMPTGRTLA,LLILMTTSKY,SKYTAPM TSY,WICCSSQMSR,TTASGWSGAS,YTAPMTSYRS,YPRSYP LTCA,YPLTCAATTA,SPCTSSSWSL,MPTGRTLASS,GPPTST PAAM,LEYPRSYPLT,GASPCTSSSW,TSSSWSLLIL,SSSWSLL ILM,YRSMPTGRTL,SKGPPTSTPA C1RL c.1051de|C p.L351f PDYRQNESHNFSGDIALLELQHSIP[p.L AAACWATSV,ELQHSIPWA,IMRPSTAAA,ATSVGLAWR,SS CRC s 351fs]WAPTSSRSVCPIMRPSTAAACW RSVCPIM,IPWAPTSSR,STAAACWAT,APTSSRSVC,CPIMR ATSVGLAWRWAG* PSTA,LELQHSIPW,LQHSIPWAP,WATSVGLAW,RPSTAAA CW,TSVGLAWRW,TAAACWATSV,CWATSVGLAW,SSRSV CPIMR,IMRPSTAAAC,SIPWAPTSSR,WATSVGLAWR,STA AACWATS,CPIMRPSTAA,RPSTAAACWA,LLELQHSIPW,LE LQHSIPWA,LQHSIPWAPT,TSSRSVCPIM,AACWATSVGL C1orf c.1612C>T p.R538 PPGYFPAGRYVVVAESPLPPGEWEL[p. GEWELCRAA,CRAAPGPAY,WELCRAAPG,LCRAAPGPAY, ACC 106 C R538C]CRAAPGPAYEEEGTPLRYQRLV WELCRAAPGP,GEWELCRAAP PSRS C1orf c.367A>G p.S123 WWHLRALGPDATSSCTKTPSALEPL[p. LEPLGSSTL,ALEPLGSSTL TGCT 167 G S123G]GSSTLQDSLEKVPRAPTLPDTLQ GSL C1orf c.2063C>A p.S688 ESFENVLKEGTEKGTQEIAEGLSEK[p.S6 IAEGLSEKY,GLSEKYGKHV,YGKHVSAEEK,EIAEGLSEKY,SE LUAD 173 Y 88Y]YGKHVSAEEKEKDKSKLWEESTAQ KYGKHVSA VK C1orf c.4360G>A p.G145 AGVGTPGALERKTSGLGQEQEEGSE[p. EEGSESQEA,QEEGSESQEA,EEGSESQEAA LUAD 173 4S G1454S]SQEAATGSGDGRQETGAAEK FRLGLS C1orf c.760G>A p.D254 PGLRDILNTWEKDLRTRFRTQNDFA[p. NLSISSEIV,RTQNDFANL,FANLSISSEI,RFRTQNDFAN,FRT LUSC 74 N D254N]NLSISSEIVTLPAVAL* QNDFANL,TQNDFANLSI C1orf c.1622G>T p.R541 LSPQKIDQALRRFRSGENMLLEPAL[p.R MLLEPALLY,NMLLEPALL,LLEPALLYL,MLLEPALLYL,LLEPA LUAD 87 L 541L]LYLKEL* LLYLK,NMLLEPALLY,EPALLYLKEL C20or c.1146A>C p.E382 LKLPLRFQRLGHLVALMALLCGDPQ[p. LLCGDPQDKV KIRC f132 D E382D]DKVAEEAAEGIHSLLHITLRLKYI TH C20or c.136de|C p.P46fs KAGRRAACRSSVSRRPLHSMPLYPP[p. HSMPLYPPT,SSTPRFCCV,RFCCVTTWR,RKRSSSWAT,KRS STAD f160 P46fs]TTSSTPRFCCVTTWRKRSSSWAT SSWATL,MPLYPPTTS,RFCCVTTWRK,TWRKRSSSWA,RKR LPG* SSSWATL,RSSSWATLPG,TSSTPRFCCV,MPLYPPTTSS,HS MPLYPPTT,TTWRKRSSSW,TPRFCCVTTW C20or c.3263G>A p.R108 LEVQMAQPNYGLELVTGSAKNGTYF[p. TYFQIHINK,FQIHINKYK,YFQIHINKY,AKNGTYFQI,GTYFQI CRC f26 8Q R1088Q]QIHINKYKMVETITCLSREPFP HINK,TYFQIHINKY,SAKNGTYFQI,YFQIHINKYK,FQIHINKY ASNY KM,AKNGTYFQIH C22or c.83C>T p.P28L ASATAAWHCPPLCLPPLPASAPTSP[p.P APTSPLNPA,LPASAPTSPL,SPLNPATRPA ACC f26 28L]LNPATRPAPGPGRRARCPQSAHP APT C22or c.96_97ins p.P32fs RPLGVFECELCTLTAPYSYVGQKPP[p.P LQFVQQAGV,MQFILLQEI,LLQEILPPL,RLGEKESSI,ALQPR CRC f40 C 32fs]QHPVDGPPGGKLCHEGSLHLRQG GAGV,GQIPGPRLV,TLHRAPGPA,GLVSGPLGA,LVSGPLGA QIPGPRLVLQFVQQAGVCGPGMQFILL A,ATGPGSCSK,RSSGGTLHR,VVQRQMPDK,GQKPPQHPV, QEILPPLCPGEHQCFSSGNSARLGEKES HLRQGQIPG,GNSARLGEK,KTQPGTRPG,GTRPGPPTC,CFS SIKEDPQPARFSDVSATGARSSGGTLHR SGNSAR,FSSGNSARL,DAAELGAAM,GPRLVLQFV,GARSS APGPACARDAAELGAAMPGLVSGPLG GGTL,GPACARDAA,MPGLVSGPL,QPRGAGVQL,SLHLRQ AALQPRGAGVQLGAATGPGSCSKRVV GQI,GKLCHEGSL,LCHEGSLHL,GVCGPGMQF,GEHQCFSS QRQMPDKTQPGTRPGPPTCPSGPRPE* G,KEDPQPARF,ARFSDVSAT,LHRAPGPAC,VSGPLGAAL,SK RVVQRQM,RQMPDKTQP,AELGAAMPG,KLCHEGSLHL,VL QFVQQAGV,GMQFILLQEI,MQFILLQEIL,ILLQEILPPL,LLQE ILPPLC,AMPGLVSGPL,RLVLQFVQQA,ELGAAMPGLV,GLV SGPLGAA,LVSGPLGAAL,RLGEKESSIK,RVVQRQMPDK,AA TGPGSCSK,SGNSARLGEK,SIKEDPQPAR,RSSGGTLHRA,GT LHRAPGPA,IPGPRLVLQF,QQAGVCGPGM,RQGQIPGPRL, GQIPGPRLVL,LQFVQQAGVC,AGVCGPGMQF,HQCFSSGN SA,IKEDPQPARF,RDAAELGAAM,AELGAAMPGL,LQPRGA GVQL,VQLGAATGPG,CSKRVVQRQM,RQMPDKTQPG,GE HQCFSSGN C22or c.55A>G p.K19E MGNILTCCINSHCGWPRG[p.K19E]ED WPRGEDAPC,GEDAPCYES,WPRGEDAPCY TGCT f43 APCYESDTDIYETVAAATSESTTV C2orf c.1368T>A p.N456 IMLEEEPSITSGESQTTYSTFSAPL[p.N4 YSTFSAPLK,STFSAPLKK,PLKKANRKK,SAPLKKANR, CLL 44 K 56K]KKANRKKLIESLSPDFCHQNKGLLLT TYSTFSAPLK,YSTFSAPLKK,STFSAPLKKA,SAPLKKANRK, FSAPLKKANR C2orf c.815C>A p.P272 VEYPICLVCLRPRSPSCPLPRYRTG[p.P2 RYRTGHRLL,RTGHRLLAF,HRLLAFPQL,RYRTGHRLLA,LPR LUAD 53 H 72H]HRLLAFPQLLPCVQGQESGPLRIGIG YRTGHRL,YRTGHRLLAF,GHRLLAFPQL,HRLLAFPQLL C2orf c.3675_3676 p.1225_ GRPQPPTLDPTSTSYESQLGQNSSS[p.1 SSSSEESPK,SSSSEESPKK,SQLGQNSSSS KIRC 71 insAGC 1226i 225_1226insS]SEESPKKDTEPGSSPCS nsS PELQGGTRRAS C2orf c.943A>C p.T315 LELRSEGVPCIASGVLVSYPSVGGA[p.T3 YPSVGGAPR,SYPSVGGAPR ACC 81 P 15P]PRPSASCQQQRAGHSDVRLSAHH HRM C3 c.2670de|C p.P890f LLHNPAFCSLATTKRRHQQTVTIPP[p.P TVTIPPSPR,IPPSPRCPF,QTVTIPPSPR,SPRCPFHMSS, STAD s 890fs]SPRCPFHMSSCR* HQQTVTIPPS C3orf c.1655G>A p.R552 RTCHALQEDEKLVKKAEKQVTLALQ[p. VTLALQQQR,QQRNLHEHK,KQVTLALQQ,QQQRNLHEH, CLL 15 Q R552Q]QQRNLHEHKVSLVENHLAGLE QVTLALQQQR,KQVTLALQQQ,LQQQRNLHEH,QQRNLHE GRALA HKV C3orf c.2219G>T p.R740 IISSQNYTSTGQLQWLLNTLYNHQQ[p. LYNHQQLGR,QQLGRGSPC,TLYNHQQLGR,HQQLGRGSPC, LUAD 20 L R740L]LGRGSPCIQCRYDSYRLLQYDLD QQLGRGSPCI SPL C3orf c.649C>T p.R217 SWLDNNGKSAVKKLKNSLPLRKELD[p. CLKDELSHQL,KELDCLKDEL,LPLRKELDCL UCEC 23 C R217C]CLKDELSHQLQLSDIRWQRSW GIAHR C3orf c.681C>A p.D227 AERRTSEQITHRLSKLSERRPSVQI[p.D2 VQIESGSSV,IESGSSVPS,SVQIESGSSV,VQIESGSSVP LUSC 30 E 27E]ESGSSVPSDQSPSVQIDSGSSVPSDQ C3orf c.997C>T p.R333 LALAQEFQMKTVTVSLEDHTFADVV[p. TFADVVWLV,WLVSNASML,HTFADVVWL,DVVWLVSNA, CRC 39 W R333W]WLVSNASMLVSMHGAQLVTT VWLVSNASM,HTFADVVWLV,WLVSNASMLV,VWLVSNA LFLPRG SML,VVWLVSNASM C3orf c.554G>A p.R185 SNMPLNNSSQEVTKDLLDMIDHTSI[p. QTIEELQGK,IDHTSIQTI,TSIQTIEEL,MIDHTSIQTI, UCEC 62 Q R185Q]QTIEELAGKIEFENELNHMCGH HTSIQTIEEL,QTIEELQGKI CQDS C3orf c.17C>T p.S6L MSAAA[p.S6L]LPASERGWKSEKLDEA AAALPASER,SAAALPASER,AALPASERGW BLCA,CESC 70 QALARSCAAR C4orf c.2398G>C p.E800 SKDTEAHISEPEDLGKIRSPPPDHV[p.E8 VQVETAREG CESC 21 Q 00Q]QVETAREGKQYWNPRNSSELSGL VNT C5orf c.10G>A p.D4N MEV[p.D4N]NINGESRSTLTTLPFPGAE EVNINGESR CRC 30 ANSPGKA C5orf c.341G>A p.R114 LFFWSFNGLLLVVDTTGKPNFISRY[p.R FISRYQIQV,ISRYQIQVGK,KPNFISRYQI,YQIQVGKNEP CRC 4 Q 114Q]QIQVGKNEPVDPVKLRQSIRTVL FNQ C5orf c.734A>G p.Q245 PRAAGAPRPRLLLRTGSLDESLGPL[p.Q SLGPLRAAA,GPLRAAAGF,RAAAGFVQTA,ESLGPLRAAA,D ACC 65 R 245R]RAAAGFVQTALARKLSPEAPAPS ESLGPLRAA SAT C6orf c.2171A>C p.K724 RTGAINECVTFIFNRYAKKLQVSRH[p.K KLQVSRHTK,VSRHTKFGY,HTKFGYGVL,LQVSRHTKF,RHT CRC 170 T 724T]TKFGYGVLVTRVASTAAGGIALKK KFGYGV,TKFGYGVLV,KLQVSRHTKF,KKLQVSRHTK,VSRH SG TKFGYG,HTKFGYGVLV,QVSRHTKFGY,RHTKFGYGVL,TKF GYGVLVT C6orf c.172_173 p.P58fs GMSEKAIEKEIRQLLEKNEPQRPPP[p. AVSSPYSCV,EPQRPPPAV,PPPAVSSPY,RPPPAVSSPY STAD 89 insC P58fs]AVSSPYSCV* C7 c.2059C>A p.R687 GMSLEGPSAFLCGSSLKWSPEMKNA[p. EMKNASCVQK,SPEMKNASCV LUAD S R687S]SCVQKENPLTQAVPKCQRWEK LQNSR C7orf c.389de|G p.G130 GSSSEEEDSGKQALAPGLSPSQRPG[p. SQRPGVPAL,AGALRRRRK,GALRRRRKR,ALRRRRKRM,RP STAD 49 fs G130fs]VPALPVAGALRRRRKRMC* GVPALPV,GLSPSQRPGV,VAGALRRRRK,SPSQRPGVPA,RP GVPALPVA,VPALPVAGAL,ALRRRRKRMC,SQRPGVPALP C7orf c.535de|C p.L179f RARELTVQKAEALMRELDEEGSDPP[p. RLSKGFQLL,VMAGSVPSA,NLLWREMSI,CLRPHRVQL,EM STAD 50 s L179fs]CRGGPSASDRCCSCSPSGFSAG SIFLPGI,LSKGFQLLR,MSIFLPGIF,RPFHVQLLR,RVQLLRR RGRCPVQGCLRPHRVQLLRRWGPGSP WG,RWWGPGSPA,LWREMSIFL,TVMAGSVPS,APEPRKG AGQRLSKGFQLLRWWGPGSPAPEPRK PF,WPVTAVTVM,GPSSPRNLL,LLWREMSIF,RRWGPGSPA, GPFPPPDPPWPVTAVTVMAGSVPSAQ QRLSKGFQL,SKGFQLLRW,KGFQLLRWW,LESPGPLAL,RE SVDALESPGPLALEGPSSPRNLLWREM MSIFLPG,DPPWPVTAV,TVMAGSVPSA,LLWREMSIFL,FSA SIFLPGIF* GRGRCPV,CLRPHRVQLL,RLSKGFQLLR,REMSIFLPGI,RGR CPVQGCL,RPHRVQLLRR,GSPAGQRLSK,CSPSGFSAGR,LA LEGPSSPR,FPPPDPPWPV,TAVTVMAGSV,GPGSPAGQRL, VPSAQSVDAL,SPRNLLWREM,EMSIFLPGIF,RCCSCSPSGF, LRRWGPGSPA,RRWGPGSPAG,GQRLSKGFQL,QRLSKGFQ LL,LSKGFQLLRW,FQLLRWWGPG,LRWWGPGSPA,ALESP GPLAL,LEGPSSPRNL,RNLLWREMSI,NLLWREMSIF,CPVQ GCLRPH,WPVTAVTVMA,PPWPVTAVTV,GPFPPPDPPW, GPSSPRNLLW C7orf c.88G>A p.E30K SKELQGATHRYAPCDWYYHVPVKRS[p. HVPVKRSKK,KKAVDAPPA,YYHVPVKRSK,RSKKAVDAPP,V HNSC 57 E30K]KKAVDAPPASQIPGLSNLGDSHS PVKRSKKAV ENL C7orf c.418G>T p.G140 HQHILTQHGYTVVIAEERLNAGLGP[p. RLNAGLGPW,RLNAGLGPWL LUAD 58 W G140W]WLLEQGDLGSWDLLICLSSKK AEGTP C7orf c.713G>T p.R238 PSVCLDQGMQLKPSTSSHLLKTVKP[p. LLKTVKPLV,KTVKPLVWK,HLLKTVKPL,LKTVKPLVW,HLLK LUAD 58 L R238L]LVWKPGDWSREQLNETTVLAP TVKPLV,LVWKPGDWSR,SHLLKTVKPL,LLKTVKPLVW HETIF C7orf c.28G>A p.A10T MWTEEAGAT[p.A10T]TEAQESGIRNK EEAGATTEA,TEEAGATTEA CRC 63 SSSSSQIPVVGVVTE C9orf c.1024de|C p.P342f GYETHLETTGHKKMPQAFEPPMPPP[p. LALKEDLLY,ALKEDLLYL,SLQCQSLAL,KLALKEDLL,QLLCQN STAD 131 s P342fs]ANPQLLCQNPEKLALKEDLLYL PEK,MPPPANPQL,ERNLRPLSL,YLRTSGEPW,CQNPEKLAL, RTSGEPWDTERNLRPLSLQCQSLALP* FEPPMPPPA,QLLCQNPEKL,KLALKEDLLY,CQNPEKLALK,L YLRTSGEPW,ALKEDLLYLR,MPPPANPQLL,RPLSLQCQSL,L ALKEDLLYL,TERNLRPLSL,LSLQCQSLAL,GEPWDTERNL C9orf c.406C>T p.R136 ITNHREKKLQQSTKYWCLNQSAESL[p. ESLWICAMR,NQSAESLWI,AESLWICAM,QSAESLWICA,CL BRCA 174 W R136W]WICAMRGGENRPPARVQSSS NQSAESLW,SAESLWICAM EELELR CABP5 c.433de|C p.R145f NGDGEITLVELQQAMQRLLGERLTP[p. RLSGRLMLM,LMLMETAQL,MLMETAQLT,RLTPGRSLR,RS STAD s R145fs]GRSLRLSGRLMLMETAQLTLKS LRLSGRL,SLRLSGRLM,ERLTPGRSL,LRLSGRLML,LMETAQ L* LTL,RLMLMETAQL,MLMETAQLTL,RLTPGRSLRL,LMETAQ LTLK,RSLRLSGRLM,SLRLSGRLML,SGRLMLMETA,ETAQLT LKSL,GERLTPGRSL,LRLSGRLMLM CACH c.2159C>A p.S720 SLMDKAFDPTRRQWYLHAVANPGLI[p. AVANPGLIY,LIYLTGPYL,YLTGPYLDV,GLIYLTGPY,VANPGL CRC D1 Y S720Y]YLTGPYLDVGGAGYVVTI IYL,AVANPGLIYL,GLIYLTGPYL,IYLTGPYLDV,HAVANPGLIY SHTIHSSS CACN c.1994C>T p.T665 NFDEGTPPTNFDTFPAAIMTVFQIL[p. LMGEDWNEV,IMWFQILM,FQILMGEDW,MGEDWNEV CRC A1A M T665M]MGEDWNEVMYDGIKSQGGVQ M,MGEDWNEVMY,ILMGEDWNEV,LMGEDWNEVM,VF GGMVFS QILMGEDW,AIMTVFQILM CACN c.2315C>A p.S772 EVSPLSAANMSIAVKEQQKNQKPAK[p. PAKYVWEQR,NQKPAKYVW,YVWEQRTSEM,QQKNQKPA LUAD A1A Y S772Y]YVWEQRTSEMRKQNLLASREA KY LYNEM CACN c.2129C>T p.5710 RRSTFDNFPQSLLTVFQILTGEDWN[p.S ILTGEDWNL,LTGEDWNLV,GEDWNLVMY,NLVMYDGIM, UCEC A1C L 710L]LVMYDGIMAYGGPSFPGMLVCIY TGEDWNLVMY,ILTGEDWNLV,LVMYDGIMAY,LTGEDWN FII LVM CACN c.3218G>T p.R107 AKSNPEECRGLFILYKDGDVDSPVV[p.R SPVVLERIW,DVDSPVVLER,LERIWQNSDF LUAD A1D 3L 1073L]LERIWQNSDFNFDNVLSAMMA LFTVS CACN c.1055C>A p.A352 AKGITDYKKGFSFAFEQLLNYNVSR[p.A RENCNKIIM,RENCNKIIML LUAD A2D1 E 352E]ENCNKIIMLFTDGGEERAQEIFNK YN CACN c.994G>A p.A332 CLNGTLVQADRTNKEHFREHLDKLF[p. KLFTKGIGM,REHLDKLFT,KLFTKGIGML CRC A2D3 T A332T]TKGIGMLDIALNEAFNILSDFNH TGQ CACN c.1823G>A p.R608 ASHRDHNHRDETHGSSDHRHRESRH[p. RHRESRHHSR,RESRHHSRDV CRC B2 H R608H]HSRDVDREQDHNECNKQRSR HKSKDR CACN c.400G>A p.V134I ILSVTLLFFGGLCVAASEFHRSRHN[p.V1 RSRHNIILS,FHRSRHNII,HRSRHNIIL,SRHNIILSA,RSRH CRC G3 341]IILSAGIFFVSAGLSNIIGIIVYISA NIILSA,EFHRSRHNII,FHRSRHNIIL,SEFHRSRHNI CACN c.413C>T p.A138 TLLFFGGLCVAASEFHRSRHNVILS[p.A1 ILSVGIFFV,VILSVGIFF,NVILSVGIF,SRHNVILSV, CRC G3 V 38V]VGIFFVSAGLSNIIGIIVYISANAGD VILSVGIFFV,RSRHNVILSV,LSVGIFFVSA,NVILSVGIFF, RHNVILSVGI,HNVILSVGIF CACN c.694C>T p.R232 LRAKSHSEFLKKSTFARLPPYRYRF[p.R2 RYRFWRRSS,RFWRRSSSR,PPYRYRFWR,PYRYRFWRR,YR LUAD G3 W 32W]WRRSSSRSTEPRSRDLSPISKGFH FWRRSSS,LPPYRYRFW,RLPPYRYRFW,RYRFWRRSSS,RF TI WRRSSSRS,LPPYRYRFWR,PPYRYRFWRR,YRYRFWRRSS CACN c.361G>A p.G121 MIRSATPFPLVSLFFMFIGFILNNI[p.G1 FILNNIRHI,NIRHIRPHR,ILNNIRHIR,RHIRPHRTI, CRC G5 R 21R]RHIRPHRTILAFVSGIFFILSGLSLV GFILNNIRHI,FIGFILNNIR,FILNNIRHIR, NNIRHIRPHR,RHIRPHRTIL CACN c.437T>G p.V146 LRVVRASSIFPILSAILLLLGGVCV[p.V14 LLGGVCVGA,CVGASRVYK,GASRVYKSK,VCVGASRVY,LLL BLCA G8 G 6G]GASRVYKSKRNIILGAGILFVAAGLS GGVCVGA,VGASRVYKSK,GVCVGASRVY CADM c.569C>T p.S190 NCTAMASKPATTIRWFKGNTELKGK[p. LEVEEWSDM,TELKGKLEV,LEVEEWSDMY CRC 1 L S190L]LEVEEWSDMYTVTSQLMLKVH KEDDG CADP c.2875C>A p.R959 DAALEVQPPDTWDSFPLFQLLNDFL[p. LNDFLSTDY,FLSTDYNLC,DFLSTDYNL,LLNDFLSTDY,STDY LUAD S S R959S]STDYNLCNGKFHKHLQDLFAPL NLCNGK,FQLLNDFLST,NDFLSTDYNL WRY CADP c.3217G>A p.A107 PSWMAAIYDADNGSGTSEDLFWKLD[p. KLDTLQTFI,WKLDTLQTF,KLDTLQTFIR,FWKLDTLQTF,WK CRC S 3T A1073T]TLQTFIRDLHWPEEEFGKHL LDTLQTFI EQRLKL CALB2 c.180G>C p.K60N YIEGKELENFFQELEKARKGSGMMS[p. NSDNFGEKM,GMMSNSDNF,SNSDNFGEK,MSNSDNFGE CESC K60N]NSDNFGEKMKEFMQKYDKNSD K,SGMMSNSDNF GKIEM CALB2 c.772C>T p.R258 KEMNIQQLTNYRKSVMSLAEAGKLY[p. KLYCKDLEI,KLYCKDLEIV,LYCKDLEIVL LUAD C R258C]CKDLEIVLCSEPPM* CALCB c.242G>C p.R81T DYVQMKASELKQEQETQGSSSAAQK[p. AQKTACNTA,KTACNTATCV,AQKTACNTAT CESC R81T]TACNTATCVTHRLAGLLSRSGG MVKS CALD1 c.1018G>A p.E340 ERMREEEKRAAEERQRIKEEEKRAA[p.E AAKERQRIK,RAAKERQRI,RAAKERQRIK CLL K 340K]KERQRIKEEEKRAAEERQRIKEEE KR CALN c.691G>A p.V231I LNETSGNCQTEFEGVHSQKQNRQTC[p. KQNRQTCIR,QNRQTCIRK,CIRKSLICA,RQTCIRKSL,IRKSLIC GBM 1 V231I]IRKSLICAFAMAFIISVMLIAANQ AF,KQNRQTCIRK,SQKQNRQTCI,CIRKSLICAF,RQTC IL IRKSLI CAMK c.392G>T p.G131 EYYSEADASHCIQQILEAVLHCHQM[p. AVLHCHQMV,VLHCHQMVV,MVVVHRDLK,AVLHCHQM LUAD 2B V G131V]VVVHRDLKPENLLLASKCKGAA VV,VLHCHQMVVV,QMVVVHRDLK,EAVLHCHQMV,HQM VKLA VVVHRDL CAMS c.1396_1397 p.T466f RHRSNSLTRVDGQPRGAAIAWPEKK[p. VPANTFCST,QACVPANTF,KKNQACVPA,WPEKKNQACV, BLCA AP1 insA s T466fs]NQACVPANTFCSTSRCEL* NQACVPANTF CAMS c.1396de|A p.T466f RHRSNSLTRVDGQPRGAAIAWPEKK[p. LLLYITLRV,LLYITLRVV,RVVKWIPAL,GLRPSQHLL,VVKWIP KICH AP1 s T466fs]PGLRPSQHLLLYITLRVVKW ALA,SAWPAPSAK,HLLLYITLR,KWIPALATA,LYITLRVVK,AS IPALATASAWPAPSAKTVWHPTLLI* AWPAPSA,SAKTVWHPT,KTVWHPTLL,RPSQHLLLY,LATAS AWPA,TVWHPTLLI,IPALATASA,WPAPSAKTV,SQHLLLYIT, VKWIPALAT,AKTVWHPTL,HLLLYITLRV,LLLYITLRVV,ALA TASAWPA,GLRPSQHLLL,YITLRVVKWI,RVVKWIPALA,WI PALATASA,LLYITLRVVK,ASAWPAPSAK,LYITLRVVKW,TLR VVKWIPA,SAKTVWHPTL,KTVWHPTLLI,LRPSQHLLLY,TAS AWPAPSA,KPGLRPSQHL,RPSQHLLLYI,IPALATASAW,WP APSAKTVW,SAHLLLYITL,LRVVKWIPAL,VKWIPALATA,AK TVWHPTLL CANT c.392A>G p.K131 RIAVIADLDTESRAQEENTWFSYLK[p. YLKRGYLTL,NTWFSYLKR,SYLKRGYLT,WFSYLKRGY,FSYLK PRAD 1 R K131R]RGYLTLSDSGDKVAVEWDKDHG RGYL,YLKRGYLTLS,SYLKRGYLTL,TWFSYLKRGY,ENTWFSY VLES LKR CAPN c.906_911 p.LV30 LHTSSELQSPSSYFASRPWVRAKGL[p. GLLGFPVLT,WVRAKGLLG,VRAKGLLGF,AKGLLGFPV,KGLL TGCT S1 de|GCTGGT 3de| LV303de|]LGFPVLTLHPPLPSGCS* GFPVL,GLLGFPVLTL,RAKGLLGFPV,WVRAKGLLGF,RPWV RAKGLL,AKGLLGFPVL CAPRI c.37G>A p.E13K MEVQVSQASLGF[p.E13K]KLTSVEKSL SLGFKLTSV,VSQASLGFK,GFKLTSVEK,SQASLGFKL,QVSQ CRC N2 REWSRLSREVIAWLCPS ASLGFK,LGFKLTSVEK,KLTSVEKSLR,SQASLGFKLT,FKLTSV EKSL CARD c.1268G>A p.R423 IEKDKYRKQIRELEEKNDEMRIEMV[p.R EMRIEMVQR,DEMRIEMVQ,IEMVQREAC,MRIEMVQREA, CRC 11 Q 423Q]QREACIVNLESKLRRLSKDSNNL IEMVQREACI,VQREACIVNL DQS CARD c.1876G>A p.E626 LDDDSHERYSFGPSSIHSSSSSHQS[p. SSSSSHQSK,HQSKGLDAY,HSSSSSHQSK,SHQSKGLDAY DLBCL 11 K E626K]KGLDAYDLEQVNLMFRKFSLER PFRP CARD c.279G>C p.E93D SKINRAGRLLDILHTKGQRGYVVFL[p. FLDSLEFYY,GYVVFLDSL,VVFLDSLEF,VFLDSLEFY,FLDSLEF DLBCL 11 E93D]DSLEFYYPELYKLVTGKEPTRRF YYP,VVFLDSLEFY,YVVFLDSLEF,RGYVVFLDSL,VFLDSLEFY STI Y,DSLEFYYPEL CARD c.3195C>G p.I1065 ANIEAVAAKNKHCLLEAGIGCTRDL[p.I LMKSNIYPI,RDLMKSNIY,MKSNIYPIV,DLMKSNIYPI,LMKS LUAD 11 M 1065M]MKSNIYPIVLFIRVCEKNIKRFR NIYPIV,GIGCTRDLMK,CTRDLMKSNI,MKSNIYPIVL KLL CARM c.605C>T p.A202 LQNHTDFKDKIVLDVGCGSGILSFF[p.A ILSFFVAQA,FVAQAGARK,SFFVAQAGA,FFVAQAGAR,LSF GBM 1 V 202V]VAQAGARKIYAVEASTMAQHAE FVAQAG,GILSFFVAQA,FVAQAGARKI,SFFVAQAGAR,VA VLVK QAGARKIY,CGSGILSFFV,LSFFVAQAGA CASC1 c.161G>A p.R54Q ERRLKEEEEARLKYEKEEMERLEIQ[p. RLEIQQIEK,MERLEIQQI CRC R54Q]QIEKEKWHRLEAKDLERRNEEL EELY CASC3 c.1808C>T p.P603 MNLPHPGLHPHQTPAPLPNPGLYPP[p. GLYPPLVSM,NPGLYPPLV,GLYPPLVSMS,LPNPGLYPPL STAD L P603L]LVSMSPGQPPPQQLLAPTYFSA PGVM CASC3 c.1934C>T p.P645 TYFSAPGVMNFGNPSYPYAPGALPP[p. YAPGALPPL,LPPLPPPHL,ALPPLPPPHL,PYAPGALPPL,LPPL STAD L P645L]LPPPHLYPNTQAPSQVYGGVTY PPPHLY YNPA CASC3 c.1973>T p.S658 PSYPYAPGALPPPPPPHLYPNTQAP[p.S NTQAPLQVY,LYPNTQAPL,LQVYGGVTY,APLQVYGGV,HL STAD L 658L]LQVYGGVTYYNPAQQQVQPKPS YPNTQAPL,LQVYGGVTYY,QAPLQVYGGV,YPNTQAPLQV PPRR CASC3 c.695C>T p.S232 RQRKLWKDEGRWEHDKFREDEQAPK[p. KFRQELIAL,APKFRQELI,REDEQAPKF,FRQELIALY,KFRQEL STAD F S232F]FRQELIALYGYDIRSAHNPDDI IALY,EQAPKFRQEL KPRR CASD c.2341de|T p.F781f DLAQIIIPKDNSSLLKRLACIAAFF[p. DSSSYHPFK,INQNIRFQK,AFFVDSSSY,LACIAAFFV,HPFKIN STAD 1 s F781fs]VDSSSYHPFKINQNIRFQKF* QNI,VDSSSYHPF,FKINQNIRF,NQNIRFQKF,FVDSSSYHPF, RLACIAAFFV,KINQNIRFQK,INQNIRFQKF,AAFFVDSSSY,H PFKINQNIR,DSSSYHPFKI CASP1 c.13C>T p.R5W MSNP[p.R5W]WSLEEEKYDMSGARLA NPWSLEEEKY CRC 4 LILCVTKARE CASP5 c.67de|A p.R23fs MAAVPRVEGVFIFLIEDSGKKK[p. RILKLCSKV,KVSFRVDWI,KLCSKVSFR,KKKGVRILK,GKKKG KIRC R23fs]GVRILKLCSKVSFRVDWITS* VRIL,KKGVRILKL,LKLCSKVSF,SKVSFRVDW,KLCSKVSFRV, GVRILKLCSK,SGKKKGVRIL,ILKLCSKVSF,KKKGVRILKL,SKV SFRVDWI CASP8 c.1413de|A p.R471f YEVSNKDDKKNMGKQMPQPTFTLRK[p. LLIDGAILF,LIDGAILFV,ILFVLFCFV,FVLFCFVFL,TLRKNLSSL, STAD s R471fs]NLSSLLIDGAILFVLFCFV FVFLRQNLA,VLFCFVFLR,CSGVISAHR,SGVISAHRK,RVAG FLRQNLALSPRLECSGVISAHRKLRLPG TTGAR,DGAILFVLF,AILFVLFCF,LFVLFCFVF,CFVFLRQNL,V SGHSPASASRVAGTTGARHHTWLIF* FLRQNLAL,RQNLALSPR,VISAHRKLR,KLRLPGSGH,GARHH TWLI,LPGSGHSPA,LRKNLSSLL,RKNLSSLLI,ARHHTWLIF,I DGAILFVL,FTLRKNLSSL,NLSSLLIDGA,LLIDGAILFV,LIDGAI LFVL,AILFVLFCFV,FVFLRQNLAL,TLRKNLSSLL,RLECSGVIS A,RLPGSGHSPA,FVLFCFVFLR,CSGVISAFIRK,IDGAILFVLF, GAILFVLFCF,ILFVLFCFVF,RQNLALSPRL,KLRLPGSGHS,SG HSPASASR,ASRVAGTTGA,GARHHTWLIF,RVAGTTGARH, ECSGVISAHR,GVISAHRKLR,QPTFTLRKNL,SLLIDGAILF CAST c.1917T>A p.D639 DDALDKLSDSLGQRQPDPDENKPME[p. MEEKVKEKA CLL E D639E]EKVKEKAKAEHRDKLGERDDTI PPEY CATSP c.1274C>T p.T425 MIVEEVRAIRFNQEQESEVLNRRSS[p.T SMSGSLETT,EVLNRRSSM,RRSSMSGSL,NRRSSMSGSL,SE KIRC ER4 M 425M]MSGSLETTSSKDIRQMSQQQDL VLNRRSSM LSAL CBFB c.454G>A p.E152 FDEERAQQEDALAQQAFEEARRRTR[p. EARRRTRKF,RTRKFEDRDR,RKFEDRDRSH,EEARRRTRKF CRC K E152K]KFEDRDRSHREEMEVRVSQLLA VTGK CBLL1 c.413de|A p.E138f PIKIYGRMIPCKHVFCYDCAILHEK[p. ILCSELSSV,VLSSCVALF,CLRETYRLI,LSSCVALFK,CVALFKG STAD s E138fs]REIRCVQAVVILCSELSSVHEVL AR,HICLRETYR,GAREHICLR,TYRLISTIA,ILHEKREIR,EIRCV SSCVALFKGAREHICLRETYRLISTIAI* QAVV,ELSSVHEVL,EVLSSCVAL,ETYRLISTI,REIRCVQAV,R CVQAVVIL,SELSSVFIEV,HEVLSSCVA,ALFKGAREH,EHICLR ETY,RETYRLIST,YRLISTIAI,REHICLRET,HEKREIRCV, VILCSELSSV,SVHEVLSSCV,ALFKGAREHI,VLSSCVALFK, TYRLISTIAI,EHICLRETYR,ETYRLISTIA,EVLSSCVALF, REIRCVQAVV,SELSSVHEVL,HEVLSSCVAL,REHICLRETY, RETYRLISTI CBLN3 c.206de|C p.P69fs ECLVVCEPGRAAAGGPGGAALGEAP[p. AMAPVGPST,ATTMSQQGK,QGKPAMAPV,APLGEWHLL, STAD P69fs]LGEWHLLRSEATTMSQQGKPA MSQQGKPAM,APVGPSTST,LLRSEATTM,GAALGEAPL,GE MAPVGPSTSTRSW* WHLLRSE,GPSTSTRSW,EAPLGEWHLL,TTMSQQGKPA,KP AMAPVGPS,TMSQQGKPAM,HLLRSEATTM,GEAPLGEW HL,GEWHLLRSEA,QQGKPAMAPV,AMAPVGPSTS CBWD c.304_305 p.E102f ESGEGSALEKSLAVSQGGELYEEWL[p. GELYEEWLGT KICH 6 insG s E102fs]GT* CC2D c.3850C>T p.R128 ESQEDEKLLQATEKFQAECALKFPN[p. LKFPNCQCL,FPNCQCLTT,ALKFPNCQCL,CQCLTTVIDI,FPN CRC 2A 4C R1284C]CQCLTTVIDISGKTVFITRY CQCLTTV,AECALKFPNC LKPLNP CCDC c.3492de|C p.P116 LERDPTPCELTYKVPTRHSMSQIPP[p.P SQIPPSSPL,MSQIPPSSPL STAD 108 4fs 1164fs]SSPL* CCDC c.1250G>T p.R417 GIKGGIRRWNYFFPEELLVYDICKY[p. LVYDICKYL,VYDICKYLW,YLWCENIGR,CKYLWCENI,LLVYD LUAD 111 L R417L]LWCENIGRAFIKSNNIMILVDL ICKYL,YLWCENIGRA,LVYDICKYLW KNEVW CCDC c.22A>G p.I8V MEVKGQL[p.I8V]VSSPTFNAPAALFGE LVSSPTFNA,GQLVSSPTF,MEVKGQLVS,QLVSSPTFNA,ME KIRC 120 AAPQVKSERLR VKGQLVSS,KGQLVSSPTF CCDC c.1190G>T p.W39 IEQAQKLTATQSHLENRKQQLQQEQ[p. QQLQQEQLY,KQQLQQEQL,QEQLYLESL,QLYLESLIQA,KQ LUSC 121 7L W397L]LYLESLIQARQRLQGSHNQCLN QLQQEQLY,LYLESLIQAR,RKQQLQQEQL,QQLQQEQLYL, RQDV QQEQLYLESL,QEQLYLESLI CCDC c.2512C>T p.R838 NIYVDALLKEFEQFNRRLNEVSKRV[p.R CIPLPVSNI,VSKRVCIPL,KRVCIPLPV,NEVSKRVCI,EVSKRVC UCEC 132 C 838C]CIPLPVSNILWEHCIRLANRTIV IPL,SKRVCIPLPV EGY CCDC c.937G>A p.E313 AEKAKPDALHGLRVHSWVLVLSGKR[p. GKRKVPENF,RKVPENFFI,WVLVLSGKRK,KRKVPENFFI,GK HNSC 135 K E313K]KVPENFFIDPFTGHSYSTQDEHF RKVPENFF LGI CCDC c.3791C>T p.S126 NTTSIKTQMELTIKDLESEISRIKT[p. KTLQADFNK,ISRIKTLQA,RIKTLQADF,SEISRIKTL,LQADFN UCEC 144A 4L S1264L]LQADFNKTELERYKELYLEEV KTEL,RIKTLQADFN,EISRIKTLQA,SRIKTLQADF KVRES CCDC c.1260de|A p.K420f KEEEKEKLWKKKELLQRAEKKKKIK[p. KIKNTGPRK,KNRSGKKWK,RKNRSGKKW STAD 148 s K420fs]NTGPRKNRSGKKWK* CCDC c.1463C>A p.P488 ILPKYQDQNFLPKDQNFLSRDQHVL[p. LSRDQHVLH,LSRDQHVLHK CLL 15 H P488H]HKDQDILPKYQDQNFLPKDQN FLSRD CCDC c.457G>C p.E153 GYKKEISKLYQDMQRKVELNEEKHK[p. KHKQLIEKK,KQLIEKKEM,QLIEKKEMEI,HKQLIEKKEM CESC 152 Q E153Q]QLIEKKEMEISELNAKLRSQEKE KQN CCDC c.598_599 p.P200f QWDGAALRLHARHKEQQRQFGLTPP[p. LTPPWIFEA,RQFGLTPPW,QFGLTPPWI,FGLTPPWIF,RQF STAD 153 insC s P200fs]WIFEATSP* GLTPPWI,GLTPPWIFEA,QFGLTPPWIF,QRQFGLTPPW CCDC c.599de|C p.P200f QQWDGAALRLHARHKEQQRQFGLTP[p. QRQFGLTPL,RQFGLTPLD,RQFGLTPLDL,QQRQFGLTPL STAD 153 s P200fs]LDL* CCDC c.994G>T p.A332 KELSDIWSAVHVLQNSIDSLTLCSG[p.A TLCSGSCPK,TLCSGSCPKA,LTLCSGSCPK,GSCPKASSLR TGCT 159 S 332S]SCPKASSLRGHKGHQCLSPPLPS WDS CCDC c.15058G>T p.D502 GYTLSNSKGPVQPTAQGEEKGGLRI[p. YMEDKMLPK,GLRIYMEDK,EEKGGLRIY,LRIYMEDKM,RIY UCEC 168 0Y D5020Y]YMEDKMLPKCTDLKAKQLLLS MEDKML,IYMEDKMLPK,GEEKGGLRIY,EEKGGLRIYM DILNT CCDC c.485A>G p.K162 LDDCIFNMVLLKVPSSLSAEELEAI[p.K1 AIRLIRFGK,RLIRFGKKK,ELEAIRLIR,LEAIRLIRF,EELE STAD 169- R 62R]RLIRFGKKKNTHSLFVFIIPENFKGC AIRLI,AEELEAIRL,AIRLIRFGKK,EAIRLIRFGK,EELEAI SOHL RLIR,AEELEAIRLI H2 CCDC c.620G>T p.R207 KLRMEQEEELKDMSKIILNAKCHAI[p.R ILDAQILEK,LNAKCHAIL,HAILDAQIL,ILNAKCHAIL, LUAD 19 L 207L]LDAQILEKQAIQKELDTEEKRLDQ AILDAQILEK MM CCDC c.836G>T p.R279 RIRGRRQIVEQMEKNQEERSLLAEQ[p. LEQEKEQML,EERSLLAEQL LUAD 19 L R279L]LEQEKEQMLEYMEQLQEEDLK DMERR CCDC c.626G>T p.R209I AQNDLVFEAVQDKGNMEQAILEMKK[p. IFEARQGEF,EMKKIFEAR,AILEMKKIF,LEMKKIFEA, UCEC 36 R209I]IFEARQGEFIEMKSNLKHLEVL KIFEARQGEF,QAILEMKKIF VAQQ CCDC c.172C>T p.R58C FVVHTVQFLNRFSTVCEEKLADLSL[p.R KLADLSLCI,ADLSLCIQQI CESC 53 58C]CIQQIETTLNILDAKLSSIPGLDDVT CCDC c.689G>A p.R230 GQKWEHFITAPKTKKFKIPTMRVTN[p. PTMRVTNHK,RVTNHKPSR,VTNHKPSRR,RVTNHKPSRR CRC 60 H R230H]HKPSRRGSTLSLSRASGGSSPQS SMI CCDC c.1319A>C p.N440 IEQLEREGNEEEIQRENYQDNISSM[p.N NISSMTISI,TISIQNTWK,MTISIQNTW,YQDNISSMT,YQDN CLL 79 T 440T]TISIQNTWKHLHADRIGRGSKAE ISSMTI,MTISIQNTWK,SMTISIQNTW DED CCDC c.776G>T p.R259I NRERKCKLKDQSDKEEGTRDISSPK[p.R ILRDRQALF,DISSPKILR,RDISSPKIL,KILRDRQAL, CRC 81 259I]ILRDRQALFPAKVTNVSLLEKFERSE GTRDISSPKI,KILRDRQALF CCDC c.2031_2032 p.K677f ITCEKIEALEQENSELERENRKLKK[p.K6 RENRKLKKNI STAD 88A insA s 77fs]NIG* CCDC c.5553_5554 p.P1851 QKLGAPEALGGRETGSHTLQSPAPP[p. LQSPAPPQL,TLQSPAPPQL CRC 88C insC fs P1851fs]QLP* CCKA c.811C>A p.L271 QKKSAKERKPSTTSSGKYEDSDGCY[p.L YMQKTRPPR,MQKTRPPRK,YEDSDGCYM,YMQKTRPPRK, LUAD R M 271M]MQKTRPPRKLELRQLSTGSSSRA MQKTRPPRKL,CYMQKTRPPR NRI CCKBR c.706G>A p.V236 SARVRQTWSVLLLLLLFFIPGVVMA[p.V FIPGVVMAM,VVMAMAYGL,VMAMAYGLI,AMAYGLISR, CRC M 236M]MAYGLISRELYLGLRFDGDSDSD MAMAYGLIS,FIPGVVMAMA,VVMAMAYGLI,MAMAYGLI SQS SR,FFIPGVVMAM,MAYGLISREL,IPGVVMAMAY CCNB c.2794G>A p.A932 ETLLKKPLALKMSTINEAVLFEDMI[p.A9 VLFEDMITL CLL 3 T 32T]TLNEKPTTGKELSFKEPLALQESPTY CCR5 c.554G>T p.S185I SLPGIIFTRSQKEGLHYTCSSHFPY[p.S18 SSHFPYIQY,HFPYIQYQF,IQYQFWKNF,FPYIQYQFW, KIRC 5I]IQYQFWKNFQTLKIVILGLVLPLLVM CSSHFPYIQY,YTCSSHFPYI,SHFPYIQYQF,HFPYIQYQFW, YIQYQFWKNF CCZ1 c.642G>C p.E214 IFGGISFFPLDKMTYLKIQSFINRM[p.E2 FINRMDESL,RMDESLNIV,DESLNIVKY,RMDESLNIVK, KIRC D 14D]DESLNIVKYTAFLYNDQLIWSGLE SFINRMDESL,MDESLNIVKY QD CD101 c.1781G>A p.R594 SDLKVPLTVTWQFQPASSHIFHQLI[p.R HIFHQLIQI,IQITHNGTI,SHIFHQLIQI CRC Q 594Q]QITHNGTIEWGNFLSRFQKKTKV SQS CD101 c.847G>T p.D283 PDETWMFITKKQTDQTTLRIQPAVK[p. RIQPAVKYF,KYFQVNITA,AVKYFQVNI,LRIQPAVKY,QPAV CRC Y D283Y]YFQVNITADSLFAEGKPLELVCL KYFQV,IQPAVKYFQV,TLRIQPAVKY,LRIQPAVKYF,VKYFQ VVS VNITA CD109 c.1409T>A p.L470 AYFLGSKSSMAVHSLFKSPSKTYIQ[p.L4 KTYIQQKTR,PSKTYIQQK,QQKTRDENIK,IQQKTRDENI CLL Q 70Q]QKTRDENIKVGSPFELVVSGNKRL KE CD163 c.2161G>A p.V721 SDMELRLVGGSSRCAGKVEVNVQGA[p. VEVNVQGAM,MGILCANGW,EVNVQGAMGI,KVEVNVQ GBM LI M V721M]MGILCANGWGMNIAEVVCR GAM,VQGAMGILCA,AMGILCANGW QLECGSA CD180 c.683A>C p.N228 SLNFNGNNVKGIELGAFDSTIFQSL[p.N LTFGGTPNL,STIFQSLTF,SLTFGGTPNL,FQSLTFGGTP CRC T 228T]TFGGTPNLSVIFNGLQNSTTQSL WLG CD1B c.122G>T p.W41L GNSEHAFQGPTSFHVIQTSSFTNST[p. FTNSTLAQT,SSFTNSTLA,TSSFTNSTL,LAQTQGSGW,QTSS LUAD W41L]LAQTQGSGWLDDLQIHGWDSD FTNSTL,TSSFTNSTLA,TLAQTQGSGW SGTAI CD1C c.265C>T p.R89C TIIFLHNWSKGNFSNEELSDLELLF[p.R8 LSDLELLFC,ELLFCFYLF,LFCFYLFGL,CFYLFGLTR, SKCM 9C]CFYLFGLTREIQDHASQDYSKYPFEV SDLELLFCF,LELLFCFYL,LSDLELLFCF,LLFCFYLFGL, SDLELLFCFY,FCFYLFGLTR,LELLFCFYLF CD1D c.74de|T p.L25fs MGCLLFLLLWALLQAWGSAEVPQRL[p. RLSPSAASR,ASRSRPSPI,RSRPSPIAA,AGRAPTAWR,VPQR GBM L25fs]SPSAASRSRPSPIAAGRAPTAWR LSPSA,SPIAAGRAP,AAGRAPTAW,AASRSRPSPI,ASRSRPS GWGSCRRTAGATTRTPSAL* PIA,RSRPSPIAAG,AWRGWGSCRR,TAWRGWGSCR,EVPQ RLSPSA,VPQRLSPSAA,RPSPIAAGRA,SPIAAGRAPT,AEVP QRLSPS,IAAGRAPTAW CD1E c.253T>G p.F85V GDLQTHGWDTVLGTIRFLKPWSHGN[p. KPWSHGNVS,FLKPWSHGNV,KPWSHGNVSK,HGNVSKQE STAD F85V]VSKQELKNLQSLFQLYFHSFIQI LK VQA CD209 c.847G>A p.A283 WEWTFFQGNCYFMSNSQRNWHDSIT DSITTCKEV GBM T [p.A283T]TCKEVGAQLVVIKSAEEQNF LQLQSS CD4 c.492de|G p.Q164 TLESPPGSSPSVQCRSPRGKNIQGG[p. CLSWSSRIV,RIVAPGHAL,RTRRRWSSK,RGKNIQGGR,SSRI STAD fs Q164fs]RPSPCLSWSSRIVAPGHALSCR VAPGH,HALSCRTRR,LSWSSRIVA,SSRIVAPGHA,HALSCRT TRRRWSSK* RRR,IQGGRPSPCL,GGRPSPCLSW,SRIVAPGHAL,SPCLSW SSRI CD55 c.466G>A p.E156 PGYRREPSLSPKLTCLQNLKWSTAV[p.E NLKWSTAVK,STAVKFCKK,WSTAVKFCK,TAVKFCKKK,LK UCEC K 156K]KFCKKKSCPNPGEIRNGQIDVPG WSTAVKF,KWSTAVKFCK,WSTAVKFCKK,STAVKFCKKK,NL GIL KWSTAVKF CD7 c.521de|C p.P174f ASALPAPPTGSALPDPQTASALPDP[p.P ALPDPQQPL,DPQQPLPSL,QPLPSLRPW,SALPDPQQPL,Q KIRC s 174fs]QQPLPSLRPWR* QPLPSLRPW CD79 c.589T>C p.Y197 LFIIVPIFLLLDKDDSKAGMEEDHT[p.Y1 EEDHTHEGL,MEEDHTHEGL,HEGLDIDQTA DLBCL B H 97H]HEGLDIDQTATYEDIVTLRTGEVK WS CD79 c.589T>G p.Y197 LFIIVPIFLLLDKDDSKAGMEEDHT[p.Y1 MEEDHTDEGL DLBCL B D 97D]DEGLDIDQTATYEDIVTLRTGEVK WS CD93 c.838de|G p.D280 PLCVSPKYGCNFNNGGCHQDCFEGG[p. GMAPSSAAA,HQDCFEGGM,FEGGMAPSS,FEGGMAPSSA STAD fs D280fs]MAPSSAAADQDSGCWMTW* CDAN c.1936_1937 p.L646f GERKQFAVVLLSLRLLAKFLGFVAF[p.L6 FLGFVAFPA,FVAFPAIPG,LGFVAFPAI,FLGFVAFPAI, KIRC 1 insC s 46fs]PAIPGA* FVAFPAIPGA,KFLGFVAFPA CDC1 c.369de|C p.N123 AYAVIYLKKTPEEAYRALLSGSNPP[p.N1 NMDFLTLRH,LLSGSNPPI,GMLPLEIAL,MLPLEIALT,LTI STAD 4A fs 23fs]IFHSGMLPLEIALTISPFSTVCRE SPFSTV,HLMWMNMNI,NIMSELKMV,IMSELKMVT,STVCRES SERDYNMDFLTLRHLMWMNMNIMSELK ER,NMNIMSELK,IFHSGMLPL,DYNMDFLTL,KMVTSTGLF, MVTSTGLFQENF* YNMDFLTLR,EIALTISPF,MNMNIMSEL,PPIFFISGML,LPLEI ALTI,LMWMNMNIM,LSGSNPPIF,LEIALTISP,RESERDYN M,SERDYNMDF,MDFLTLRHL,LRHLMWMNM,MNIMSEL KM,SELKMVTST,LKMVTSTGL,RDYNMDFLT,ALLSGSNPPI, MLPLEIALTI,ALTISPFSTV,NMDFLTLRHL,FLTLRHLMWM, HLMWMNMNIM,WMNMNIMSEL,TISPFSTVCR,MNMNI MSELK,DFLTLRHLMW,RHLMWMNMNI,TLRHLMWMN M,FSTVCRESER,DYNMDFLTLR,EIALTISPFS,NPPIFHSGML, ELKMVTSTGL,LLSGSNPPIF,LEIALTISPF,LKMVTSTGLF, FHSGMLPLEI,SGMLPLEIAL,SERDYNMDFL,RDYNMDFLTL, YNMDFLTLRH,MDFLTLRHLM,NMNIMSELKM,TSTGLFQEN F,LPLEIALTIS CDC1 c.1123C>T p.R375 GSVIGPQQQFLVMKQTNLWLEGDYF[p. LEGDYFCQKL CRC 4B C R375C]CQKLKGQENGQHRAAFSKLLS GVDDI CDC2 c.965de|A p.K322 ENLNRPRLKQVEKFKDNTIPDKVKK[p.K KVKKSIFLA,IPDKVKKSI,AKESSGRAY,KESSGRAYV,FLAKES STAD 5C fs 322fs]SIFLAKESSGRAYV* SGRA,KVKKSIFLAK,LAKESSGRAY,IFLAKESSGR, IPDKVKKSIF CDC2 c.1379de|T p.L460 ITKLDSSIISEGKISTITPAIQAFN[p.L QIQAFNHKK,AFNHKKQQQK UCS 7 fs 460fs]HKKQQQKV* CDC2 c.1665T>G p.D555 EVRRIENYRVEGMEIYSTTLWHLQK[p. TLWHLQKEV,LQKEVALSV,EVALSVLSK,WHLQKEVAL,QKE CRC 7 E D555E]EVALSVLSKDLTDMDKNSPEA VALSVL,KEVALSVLS,HLQKEVALSV,LQKEVALSVL,TTLWHL WCAAG QKEV,KEVALSVLSK CDC2 c.1712A>T p.N571 STTLWHLQKDVALSVLSKDLTDMDK[p. MDKISPEAW,KISPEAWCAA TGCT 7 I N571I]ISPEAWCAAGNCFSLQREHDIAI KFF CDC2 c.271de|A p.I91 CTTPQCKYLLAKCCVDLSKLAEGEQ[p.I9 AMMILLLSL,MMILLLSLV,LLLSLVIQL,LLSLVIQLA,SL BLCA 7 fs 1fs]SYLVECLISRKAMMILLLSLVIQLALL VIQLALL,ALLFHCWDM,CLISRKAMM,LISRKAMMI,LVE FHCWDMYIARQIGLPKDQNVTKRALV* CLISRK,IARQIGLPK,LVIQLALLF,LFHCWDMYI,MYIA RQIGL,ISRKAMMIL,KLAEGEQSY,LLFHCWDMY,YLVEC LISR,HCWDMYIAR,SRKAMMILL,RKAMMILLL,MILLL SLVI,LSLVIQLAL,DQNVTKRAL,AEGEQSYLV,GEQSYL VEC,VECLISRKA,WDMYIARQI,KLAEGEQSYL,CLISRKA MMI,KAMMILLLSL,AMMILLLSLV,MMILLLSLVI, ILLLSLVIQL,LLLSLVIQLA,LLSLVIQLAL, LLFHCWDMYI,YIARQIGLPK,YLVECLISRK,SLVIQLALLF, IQLALLFHCW,ISRKAMMILL,ALLFHCWDMY,SKLAEGEQSY, GEQSYLVECL,VECLISRKAM,SRKAMMILLL,LALLFFICWDM CDC2 c.724C>T p.P242 LESSNSKYSLNTDSSVSYIDSAVIS[p.P24 VISSDTVPL,AVISSDTVPL,DSAVISSDTV CESC,TGCT 7 S 2S]SDTVPL6TGTSILSKQVQNKPKTGRS CDC4 c.2023C>A p.P675 EQSEHYSKQLENELEGLKQKQISYS[p.P KQISYSTGV,SYSTGVCSI,KQKQISYST,KQKQISYSTG,KQISY BRCA 2BPA T 675T]TGVCSIEHQQEITKLKTDLEKKSIFY STGVC,ISYSTGVCSI CDCA c.1215de|C p.P405 GPCLRNRYGEDVRSALLDPDWVCPP[p. AIAATVGSV,FIWPSFMVM,MVMTMLRNI,TMLRNIWRA, CRC 7L fs P405fs]VVGSAIAATVGSVTAAVPQESS ATVGSVTAA,TVGSVTAAV,MTMLRNIWR,SSFIWPSFM,SF FIWPSFMVMTMLRNIWRAYKRSW* MVMTMLR,SFIWPSFMV,MLRNIWRAY,LRNIWRAYK,RNI WRAYKR,CPPVVGSAI,WPSFMVMTM,AAVPQESSF,ESSFI WPSF,VMTMLRNIW,QESSFIWPS,VPQESSFIW,DPDWVC PPV,VVGSAIAATV,ATVGSVTAAV,SSFIWPSFMV,FIWPSF MVMT,FMVMTMLRNI,MTMLRNIWRA,SAIAATVGSV,ML RNIWRAYK,PSFMVMTMLR,SFIWPSFMVM,IWPSFMVM TM,MVMTMLRNIW,TMLRNIWRAY,VMTMLRNIWR,WV CPPVVGSA,ESSFIWPSFM,WPSFMVMTML,TAAVPQESSF, IAATVGSVTA,QESSFIWPSF,DPDWVCPPVV,CPPVVGSAIA CDH1 c.727G>A p.E243 EPLDRERIATYTLFSHAVSSNGNAV[p.E VSSNGNAVK,AVSSNGNAVK,AVKDPMEILI BRCA K 243K]KDPMEILITVTDQNDNKPEFTQE VFK CDH1 c.760G>T p.D254 TLFSHAVSSNGNAVEDPMEILITVT[p.D TVTYQNDNK,MEILIVTY,YQNDNKPEF,ITVTYQNDNK,TY STAD Y 254Y]YQNDNKPEFTQEVFKGSVMEGA QNDNKPEF LPGT CDH1 c.1045G>A p.E349 DTQEGIITVKKPLDYESRRLYTLKV[p.E3 RLYTLKVKA,KVKAENTHV,LKVKAENTH,LKVKAENTHV CRC 0 K 49K]KAENTHVDPRFYYLGPFKDTTIVKI S CDH1 c.1414C>T p.R472 LDRELSQWHNLTVIAAEINNPKETT[p.R TTCVAVFVR,ETTCVAVFV,KETTCVAVF,ETTCVAVFVR,TTC LUAD 0 C 472C]CVAVFVRILDVNDNAPQFAVFYD VAVFVRI,NPKETTCVAV,KETTCVAVFV TFV CDH1 c.1731C>G p.S577 NGFNRHEISTYLLPVVISDNDYPIQ[p.S5 YPIQRSTGT,IQRSTGTLT,QRSTGTLTI,IQRSTGTLTI, LUAD 0 R 77R]RSTGTLTIRVCACDSQGNMQSCS YPIQRSTGTL AEA CDH1 c.382C>A p.R128 IIDEKTGDIHATRRIDREEKAFYTL[p.R12 TLSAQAINR,FYTLSAQAI,EKAFYTLSA,KAFVTLSAQ,YTLSA LUAD 0 S 8S]SAQAINRRTLRPVEPESEFVIKIHDI QAINR,AFYTLSAQAI,KAFYTLSAQA,TLSAQAINRR,SAQAIN RRTL,EEKAFYTLSA,REEKAFYTLS CDH1 c.1070A>C p.K357 KKPVDFETKRAYSLKVEAANVHIDP[p.K TFISNGPFK,NVHIDPTFI,ANVHIDPTF,PTFISNGPF,PTFISN STAD 1 T 357T]TFISNGPFKDTVTVKISVEDADEP GPFK,EAANVHIDPT,AANVHIDPTF,DPTFISNGPF PM CDH1 c.2020G>A p.D674 SKEDIRDNVIHYDDEGGGEEDTQAF[p. TQAFNIGAL,QAFNIGALR,NIGALRNPK,DTQAFNIGA,EEDT CRC 2 N D674N]NIGALRNPKVIEENKIRRDIKPD QAFNI,TQAFNIGALR,DTQAFNIGAL,GEEDTQAFNI SLC CDH1 c.2116C>A p.P706 PKVIEENKIRRDIKPDSLCLPRQRP[p.P7 LCLPRQRPTM,RQRPTMEDNT HNSC 2 T 06T]TMEDNTDIRDFIHQRLQENDVDP TAP CDH1 c.2161G>T p.A721 KLTPRHQTSSTLESIDVQEFIKQRL[p.A7 FIKQRLSEA,KQRLSEADL,SEADLDPSV LUAD 8 S 21S]SEADLDPSVPPYDSLQTYAYEGQR SE CDH1 c.583G>A p.A195 EMSDMGTSVLQVTATDADDPTYGNS[p. STRVVYSIL,YGNSTRVVY,NSTRVVYSI,STRVVYSILQ GBM 8 T A195T]TRVVYSILQGQPYFSVDPKTG VIRTA CDH2 c.1639G>T p.D547 QDPDRYMQQNIRYTKLSDPANWLKI[p. KIYPVNGQI,DPANWLKIY,YPVNGQITT,YPVNGQITTI,LKIY CRC Y D547Y]YPVNGQITTIAVLDRESPNVKN PVNGQI NIYN CDH2 c.1298C>A p.P433 IQIISAKDPDVTNNSIRYSIDRSSD[p.P43 SSDHGRFFY,RSSDHGRFF,HGRFFYVDI,RSSDHGRFFY,SSD LUAD 0 H 3H]HGRFFYVDITTGALMTARPLDREEF HGRFFYV,IDRSSDHGRF S CDH2 c.401C>T p.A134 IDDTTGDIHAIQRLDREERAQYTLR[p.A QYTLRVQAL,AQYTLRVQA,AQYTLRVQAL,YTLRVQALDR,R CRC 0 V 134V]VQALDRRTGRPMEPESEFIIKIQD AQYTLRVQA,TLRVQALDRR IN CDH2 c.1207G>A p.V403 EGLNSMFEVYLVGNNSHHFIISPTS[p.V HFIISPTSI,IQGKADIRI,IISPTSIQGK,HHFIISPTSI STAD 3 I 403I]IQGKADIRIRVAIPLDYETVDRYDF D CDH2 c.3395T>A p.F113 ASVPEDIPEGHSILQLKATDADEGE[p.F ATDADEGEY,EYGRVWYRI,YGRVWYRIL,DEGEYGRVW,EY KIRC 3 2Y 1132Y]YGRVWYRILHGNHGNNFRIHV GRVWYRIL,KATDADEGEY,EGEYGRVWYR,GEYGRVWYRI, SNGLL DEGEYGRVWY CDH2 c.531C>A p.F177 FIVNATDPDLGAGGSVLYSFQPPSQ[p.F FQPPSQLFA,SFQPPSQLF,QLFAIDSAR,YSFQPPSQL,SQLFA CRC 3 L 177L]LFAIDSARGIVTVIRELDYETTQAY IDSA,QPPSQLFAI,FQPPSQLFAI,LYSFQPPSQL,YSFQPPSQL Q F,SFQPPSQLFA,SQLFAIDSAR CDH6 c.709C>A p.Q237 SETGIIKTALLNMDRENREQYQVVI[p.Q KAKDMGGQM,REQYQWIKA,YQVVIKAKDM,IKAKDMGG LUAD K 237K]KAKDMGGQMGGLSGTTTVNITL QM TDVN CDH7 c.673C>A p.Q225 PYFSVEPKTGVIKTALPNMDREAKD[p. KYLLVIQAK,EAKDKYLLV,REAKDKYLL,AKDKYLLVI,NMDRE HNSC K Q225K]KYLLVIQAKDMVGQNGGLSGT AKDKY,EAKDKYLLVI,REAKDKYLLV TSVTV CDH9 c.1569C>A p.F523 ENAKPGQLIQTVSVMDKDDPPRGHK[p. LFFEPVPEF,KLFFEPVPEF,RGHKLFFEPV CRC L F523L]LFFEPVPEFTLNPNFTIVDNKDN TAG CDHR c.652A>G p.R218 QAGATLDYERSRTHYITVVAKDGGG[p. GLHGADVVF,GGLHGADVVF MM 1 G R218G]GLHGADVVFSATTTVTVNVED VQDMA CDK1 c.237_239 p.E79 SPYRREDSMEDRGEEDDSLAIKPPQ[p.E SLAIKPPQM,AIKPPQMSR,AIKPPQMSRK,LAIKPPQMSR HNSC 1B de|AGA de| 79de|]MSRKEKVHHRKDEKRKEKCRHH SHSAEG CDK1 c.2638C>A p.R880 DFGLARLYSSEESRPYTNKVITLWY[p.R8 TLWYSPPEL,LWYSPPELL,WYSPPELLL,ITLWYSPPEL,TLWY LUAD 3 S 50S]SPPELLLGEERRTPAIDVWSCGCIL SPPELL,LWYSPPELLL G CDK1 c.322C>T p.R108 GSDGESDQASATSSDEVQSPVRVRM[p. RMCNHPPRK,RVRMCNHPP,RVRMCNHPPR,RMCNHPPR CRC 6 C R108C]CNHPPRKISTEDINKRLSLPADI KI RLP CDK5 c.4776C>G p.H159 LDEEHRRLREASGEGWKGQDPFRDL[p. RDLQSLLMEI,LQSLLMEIQA,DPFRDLQSLL KIRC RAP2 2Q H1592Q]QSLLMEIQALRLQLERSIETSS TLQS CDKAL c.1226_1227 p.P409 YKFPSLFINQFYPRPGTPAAKMEQV[p.P KMEQVLAQV,AAKMEQVLA,AKMEQVLAQ,MEQVLAQVK, TGCT 1 CA>TG L 409L]LAQVKKQRTKDLSRVFHSYSPYD KMEQVLAQVK,LAQVKKQRTK,QVLAQVKKQR,TPAAKME HKIG QVL,AKMEQVLAQV CDKN c.247C>T p.H83Y RVAELLLLHGAEPNCADPATLTRPV[p.H VYDAAREGF,LTRPVYDAA,TLTRPVYDAA,LTRPVYDAAR,D HNSC 2A 83Y]YDAAREGFLDTLVVLHRAGARLDV PATLTRPVY RD CDKN c.322G>T p.D108 HDAAREGFLDTLVVLHRAGARLDVR[p. RYAWGRLPV,GARLDVRYA,AGARLDVRY,ARLDVRYAW,R LUSC 2A Y D108Y]YAWGRLPVDLAEELGHRDVAR AGARLDVRY,RLDVRYAWGR,GARLDVRYAW,VRYAWGRL YLRAA PV,YAWGRLPVDL CDR1 c.92T>C p.V31A DVDFLEDVPLLEDIPLLEDVPLLED[p.V3 PLLEDAPLL,VPLLEDAPL,APLLEDTSRL,LEDVPLLEDA,VPLL KIRP 1A]APLLEDTSRLEDINLMEDMALLEDV EDAPLL D CDYL c.179C>G p.A60G VSAPDGPSDPSISVSSEQSGAQQPP[p. AQQPPGLQV,AQQPPGLQVE TGCT A60G]GLQVERIVDKRKNKKGKTEYLVR WKG CEAC c.1918C>A p.L640 CHSASNPSPQYSWRINGIPQQHTQV[p. HTQVIFIAK,IPQQHTQVI,PQQHTQVIF,QQHTQVIFI,TQVIF CRC AM5 I L640I]IFIAKITPNNNGTYACFVSNLATG IAKI,HTQVIFIAKI,IPQQHTQVIF,QQHTQVIFIA RN CELF4 c.925G>C p.A309 YLNPMAAFAAAQMQQMAALNMNGL APAPMTPTS,LNMNGLAPA,MNGLAPAPM,ALNMNGLAP LUAD P A[p.A309P]PAPMTPTSGGSTPPGITAP A,GLAPAPMTPT,NMNGLAPAPM AVPSIPS CELSR c.1841de|G p.G614 AVDADSGENARLHYRLVDTASTFLG[p. FLGAAALGL,STFLGAAAL,STTASGWRR,GLRILPPPL,PSRST STAD 1 fs G614fs]AAALGLRILPPPLTSPSRSTTAP TAPV,TARRWSTTA,SGWRRWTTA,GWRRWTTAR,CVPSW VGSQCVPSWTARRWSTTASGWRRWT TARR,DTASTFLGA,TASTFLGAA,GAAALGLRI,AAALGLRIL, TARPP* VGSQCVPSW,SQCVPSWTA,RRWSTTASG,RWSTTASGW, RRWTTARPP,VPSWTARRW,ILPPPLTSPS,TFLGAAALGL,R WSTTASGWR,ASGWRRWTTA,SGWRRWTTAR,SQCVPS WTAR,DTASTFLGAA,TASTFLGAAA,TTAPVGSQCV,WTAR RWSTTA,SPSRSTTAPV,ASTFLGAAAL,GAAALGLRIL,RRWS TTASGW CELSR c.34_35ins p.16_17 MRSPATGVPLPTPPPP[p.16_17insP]P LPTPPPPPL,TPPPPPLLL,LPTPPPPPLL,TPPPPPLLLL ACC 2 CGC insP LLLLLLLLLPPPLLGDQVGPCRSLGSR CELSR c.50T>C p.L17P MRSPATGVPLPTPPPP[p.L17P]PLLLLL LPTPPPPPL,TPPPPPLLL,LPTPPPPPLL,TPPPPPLLLL TGCT 2 LLLPPPLLGDQVGPCRSLGS CEP15 c.61G>A p.E21K MSLDFGSVALPVQNEDEEYD[p.E21K] KEDYEREKEL CRC 2 KEDYEREKELQQLLTDLPHDMLDDDL CEP19 c.6173C>T p.S205 TEVYDLPQRPNDVQLFYGSMCKIIL[p.S SMCKIILLV,ILLVIGEFR,IILLVIGEF,GSMCKIILLV, BLCA 2 8L 2058L]LVIGEFRDCISSREFLQPSSKASLE SMCKIILLVI,IILLVIGEFR,KIILLVIGEF S CEP44 c.758C>T p.S253 VNVNPEITALQTMLAECQENLKKLT[p.S QENLKKLTL,TLIEKRLDCL,NLKKLTLIEK,CQENLKKLTL, UCEC L 253L]LIEKRLDCLEQKMKGKVMVDENT KKLTLIEKRL,QENLKKLTLI WTN CERCA c.254_260d p.A85 RARMALWCATDHNVDNTTEMLQEWL MLQEWLGAM,WLGAMTMLL,TMLLWSGGL,LLWSGGLR KIRC M e|CGGCTGT fs [p.A85fs]GAMTMLLWSGGLRASPGST A,MLLWSGGLR,RVPSTGPKK,RASPGSTQM,STQMKRVPS, QMKRVPSTGPKKGTSF* MTMLLWSGG,TQMKRVPST,LQEWLGAMT,QEWLGAMT M,LGAMTMLLW,MLQEWLGAMT,MTMLLWSGGL,MLL WSGGLRA,TMLLWSGGLR,RASPGSTQMK,EWLGAMTML L,WLGAMTMLLW,MKRVPSTGPK,EMLQEWLGAM,LQEW LGAMTM,QEWLGAMTML,LRASPGSTQM,TQMKRVPSTG, EMLQEWLGA CERS3 c.285G>T p.E95D FVASPLAKSFGIKETVRKVTPNTVL[p.E9 NTVLDNFFK,TVLDNFFKH,DNFFKHSTR,TPNTVLDNF,VTP CRC 5D]DNFFKHSTRQPLQTDIYGLAKKCNL NTVLDNF,TPNTVLDNFF T CETN3 c.189de|A p.K63 TDKDEAIDYHELKVAMRALGFDVKK[p. GFDVKKLMY,LGFDVKKLM,LGFDVKKLMY,RALGFDVKKL STAD fs K63fs]LMY* CFB c.940_941C p.R314 INVSVAIITFASEPKVLMSVLNDNS[p.R3 VLNDNSMDM,NSMDMTEVI,MSVLNDNSM,LMSVLNDNS SKCM G>AT M 14M]MDMTEVISSLENANYKDHENGT M,VLNDNSMDMT,MDMTEVISSL GTNTY CFDP1 c.386_387i p.P129 ARKKKEDELWASFLNDVGPKSKVPP[p. GPKSKVPPK,KSKVPPKYT,KSKVPPKYTS LUAD nsC fs P129fs]KYTS* CFHR5 c.1322G>A p.R441 LCKENYLLPEAKEIVCKDGRWQSLP[p.R SLPHCVEST,RWQSLPHCV,LPHCVESTA,SLPHCVESTA,LPH CESC H 441H]HCVESTAYCGPPPSINNGDTTSF CVESTAY,GRWQSLPHCV,WQSLPHCVES PLS CFI c.111de|A p.K37 CFHLRFCKVTYTSQEDLVEKKCLAK[p.K RMALQCVQL,TVNKRVWNV,AQRMALQCV,NILTSPAIK,A STAD fs 37fs]NILTSPAIKSSASHGRDALRAPVFV SHGRDALR,RAPVFVNYR,RISAQRMAL,LRAPVFVNY,VNYR NYRISAQRMALQCVQLTGEASQHTVN ISAQR,DALRAPVFV,SPAIKSSAS,SASFIGRDAL,APVFVNYRI, KRVWNVFIQGQSF* NVFIQGQSF,KKCLAKNIL,AKNILTSPA,KNILTSPAI,RDALR APVF,YRISAQRMA,SQHTVNKRV,VNKRVWNVF,RMALQC VQLT,ALRAPVFVNY,FVNYRISAQR,RAPVFVNYRI,TVNKRV WNVF,LAKNILTSPA,KNILTSPAIK,AIKSSASHGR,KSSASHG RDA,HGRDALRAPV,SASHGRDALR,EASQHTVNKR,LTSPAI KSSA,LTGEASQHTV,HTVNKRVWNV,SPAIKSSASH,SSASH GRDAL,AKNILTSPAI,GRDALRAPVF,VNYRISAQRM,YRISA QRMAL,QRMALQCVQL,VQLTGEASQH,SQHTVNKRVW, WNVFIQGQSF,VEKKCLAKNI CGB8 c.52A>G p.T18A MEMFQGLLLLLLLSMGG[p.T18A]AW AWASREMLR,GGAWASREM,GAWASREML,GAWASREM BLCA ASREMLRPRCRPINATLAVEKEGC LR,MGGAWASREM CHCH c.236C>T p.T79M PCLGGMASGPCGEQFKSAFSCFHYS[p. AFSCFHYSM,SAFSCFHYSM,CFHYSMEEIK,MEEIKGSDCV HNSC D4 T79M]MEEIKGSDCVDQFRAMQECM QKYPDL CHD3 c.1789de|C p.P597 WRWGEPPVAVPAPQQADGNPDVPPP NPDVPPPVL,KADQSESSL,VPPPVLFKA,DVPPPVLFKA,FKA STAD fs [p.P597fs]VLFKADQSESSLSSG* DQSESSL,NPDVPPPVLF CHD4 c.2924G>A p.R975 LGPHMLRRLKADVFKNMPSKTELIV[p. HVELSPMQK,IVHVELSPM,TELIVHVEL,HVELSPMQKK,LIV CRC, H R975H]HVELSPMQKKYYKYILTRNFEAL HVELSPM,MPSKTELIVH,ELIVHVELS UCEC NAR CHD5 c.2401G>A p.A801 YVVTYTGDKESRSVIRENEFSFEDN[p.A FSFEDNTIR,NTIRSGKKV,TIRSGKKVFR,EFSFEDNTIR,NTIR CRC T 801T]TIRSGKKVFRMKKEVQIKFHVLLT SGKKVF,NEFSFEDNTI SY CHDH c.119A>C p.E40A ARGALGQQQSLGARALASAGSESRD[p. AGSESRDAY,SESRDAYSY,ESRDAYSYV,RDAYSYVVV,GSES ACC E40A]AYSYVVVGAGSAGCVLAGRLTED RDAYSY,ESRDAYSYVV,DAYSYVVVGA,SAGSESRDAY,SESR PAE DAYSYV CHEK2 c.1116_1117 p.K373 LKPENVLLSSQEEDCLIKITDFGHS[p.K3 ITDFGHSEI,EILGETSLM,SEILGETSL,TDFGHSEIL, GBM CA>TG E 73E]EILGETSLMRTLCGTPTYLAPEVLVS KITDFGHSEI,EILGETSLMR,SEILGETSLM V CHEK2 c.1117A>G p.K373 LKPENVLLSSQEEDCLIKITDFGHS[p.K3 ITDFGHSEI,EILGETSLM,SEILGETSL,TDFGHSEIL, KIRC,PRAD, E 73E]EILGETSLMRTLCGTPTYLAPEVLVS KITDFGHSEI,EILGETSLMR,SEILGETSLM UCS CHIT1 c.851_852i p.P284 LILGMPTYGRSFTLASSSDTRVGAP[p.P RVWHSRPLH,RVGAPSHRV,HSRPLHQGR,PSHRVWHSR,H KIRC nsC fs 284fs]SHRVWHSRPLHQGRRDAGLL* RVWHSRPL,VGAPSHRVW,HQGRRDAGL,RVWHSRPLHQ, HSRPLHQGRR,DTRVGAPSHR,RPLHQGRRDA,SHRVWHS RPL,RVGAPSHRVW,HQGRRDAGLL CHN1 c.792G>C p.K264 CGLNVHKQCSKMVPNDCKPDLKHVK[p. DLKHVKNW,VKNVYSCDL,NVYSCDLTTL,HVKNVYSCDL LUAD N K264N]NVYSCDLTTLVKAHTTKRPM VVDMCI CHN2 c.129C>G p.I43M AEEYQPPIWKSYLYQLQQEAPRPKR[p.I RPKRMICPR,APRPKRMIC,QEAPRPKRM,KRMICPREV,RM LUSC 43M]MICPREVENRPKYYGREFHGIISR ICPREVE,MICPREVENR,QQEAPRPKRM EQ CHRN c.67_69de| p.L23de| MGSGPLSLPLALSPPRLLLLLL[p.L23 RLLLLLLSL,RLLLLLLSLL BLCA A3 CTG de|]SLLPVARASEAEHRLFERLFEDY NEIIR CHRN c.1188C>G p.S396 LIESMHKMASAPRFWPEPEGEPPAT[p. ATRGTQSLH,PPATRGTQSL LUAD A4 R S396R]RGTQSLHPPSPSFCVPLDVPAEP GPS CHRN c.1082C>A p.P361 WARVVILKYMSRVLFVYDVGESCLS[p.P ESCLSQHHSR,CLSQHHSRER,SQHHSRERDH,GESCLSQHH LUAD A9 Q 361Q]QHHSRERDHLTKVYSKLPESNLK S AAR CIC c.1521de|C p.R507 PEGNKGFGRKVFSPVIRSSFTHCRP[p.R TLSPQGPRI,WTLSPQGPR,SFTHCRPHW,SSFTHCRPH,RPH STAD fs 507fs]HWTLSPQGPRILL* WTLSPQ,SPQGPRILL,FTHCRPHWTL,RSSFTHCRPH,HWTL SPQGPR,WTLSPQGPRI,SSFTHCRPHW CIC c.3341_3342 p.A111 ITAFYSGSPAPTSSAPLAQPSQAPP[p.A AQPSQAPPK,SQAPPKPGL,HQHNPTCSH,SHHSAQGPA,A STAD insC 4fs 1114fs]KPGLHCGHQHNPTCSHHSAQ QGPASPCH,NPTCSHHSA,LAQPSQAPPK,SQAPPKPGLH,H GPASPCHCHPSPD* QHNPTCSHH CIC c.3341 p.A111 VITAFYSGSPAPTSSAPLAQPSQAP[p.A ALSPAPQQV,HLQPPFCPR,LWPPAQPHL,AWSTLWPPA,R STAD de|C 4fs 1114fs]QAWSTLWPPAQPHLQPPFCP ARQPLPLP,LPLPPQPRL,LPPQPRLAL,QPRLALSPA,AQPHL RARQPLPLPPQPRLALSPAPQQVP* QPPF,SQAPQAWST,TLWPPAQPH,QPSQAPQAW,APQA WSTLW,TLWPPAQPHL,SQAPQAWSTL,HLQPPFCPRA,RA RQPLPLPP,CPRARQPLPL,AQPSQAPQAW,QAWSTLWPP A,LPLPPQPRLA,LALSPAPQQV CIITA c.2182G>A p.E728 AESELAFPSFLLQCFLGALWLALSG[p.E7 ALWLALSGK,LWLALSGKI,ALWLALSGKI,GALWLALSGK,L UCEC K 28K]KIKDKELPQYLALTPRKKRPYDNW WLALSGKIK,KIKDKELPQY LE CILP2 c.1657G>A p.V553 VTFVDPSGEFMDAVRVLPFDPRGAG[p. GMYHEVKAM,MYHEVKAMR,RGAGMYHEVK,MYHEVKA GBM M V553M]MYHEVKAMRKKAPVILHTSQ MRK,GMYHEVKAMR,LPFDPRGAGM,AGMYHEVKAM SNTIPL CIRH1 c.749G>T p.S250 TGTLVKSHLIANADVQSIAVADQED[p.S AVADQEDIFV,IAVADQEDIF,QEDIFVVGTA HNSC A I 250I]IFVVGTAEGTVFHFQLVPVTSNSS EK CIZ1 c.2003T>C p.V668 SEPQHQQRLGEIQHMSQACLLSLLP[p. SLLPAPRDV,LLSLLPAPR,CLLSLLPAPR,SLLPAPRDVL,LPAP CRC A V668A]APRDVLETEDEEPPPRRWCNT RDVLET CQLYY CIZ1 c.266T>C p.L89P QLLQLQQLLQQSPPQAPLPMAVSRG[p. LPMAVSRGPP GBM L89P]PPPQQPQQPLLNLQGTNSASLL NGSM CKAP2 c.2050T>A p.*684 GRETDAFVCRPNAALCRVYYEADTT[p. RVYYEADTTK CLL K *684K]KEK* CKAP5 c.1727G>C p.G576 AGGPPKKGKPAAPGGAGNTGTKNKK[p. KNKKALETK,KKALETKEI TGCT A p.G576A]ALETKEIVEPELSIEVCEEKASA VLP CLCN2 c.1934_1935 p.645_ ILLGSIERSQVVALLGAQLSPARRR[p.64 QLSPARRRR,SPARRRRQH,RRRRQHMQER,SPARRRRQH KIRC insCCG 645R>R 5_645R>RR]RQHMQERRATQTSPLSD M R QEGPPTPEASV CLCNK c.371C>A p.P124 YPVALVSFSSGFSQSITPSSGGSGI[p.P1 SGIQELKTM,QELKTMLAG,QELKTMLAGV LUAD A Q 24Q]QELKTMLAGVILEDYLDIKNFGAK VV CLDN c.628G>A p.V210 CDERCRRRRKGPSAGPRRSSVSTIQ[p.V RSSVSTIQM,IQMEWPEPD,MEWPEPDLA,IQMEWPEPDL, ACC 23 M 210M]MEWPEPDLAPAIKYYSDGQHRP RRSSVSTIQM,SSVSTIQMEW,MEWPEPDLAP PPAQ CLDN c.514T>G p.S172 DFYNPLIPTNIKYEFGPAIFIGWAG[p.S1 AIFIGWAGA,FIGWAGAAL,GWAGAALVI,FIGWAGAALV,A KIRP 7 A 72A]AALVILGGALLSCSCPGNESKAGYR IFIGWAGAA,IFIGWAGAAL,GWAGAALVIL,IGWAGAALVI V CLEC1 c.650G>T p.W21 MSQPLLMFSFFWLGLSWDSSGRSWF[p. FLEDGSVPS,DSSGRSWFL,RSWFLEDGSV LUAD 2B 7L W217L]LEDGSVPSPSLFSTKELDQIN GSKGC CLEC1 c.1268G>A p.R423 GQPDNHGFGNCVELQASAAFNWNNQ NQHCKTRNR,AAFNWNNQH,AFNWNNQFICK,NWNNQH CRC 8A H [p.R423H]HCKTRNRYICQFAQEHISRW CKTR,NQHCKTRNRY GPGS* CLEC4 c.626G>A p.R209 YNESSTFWHPREPSDPNERCVVLNF[p. VLNFHKSPK,RCVVLNFHK,LNFHKSPKR,VVLNFHKSPK,VLN PRAD A H R209H]HKSPKRWGWNDVNCLGPQRS FHKSPKR,LNFHKSPKRW,NERCVVLNFH VCEMMK CLEC4 c.536G>T p.R179 QWVDQTPYNENVTFWHSGEPNNLDE[p. NLDELCAII,ELCAIINFR,DELCAIINF,GEPNNLDEL LUSC C L R179L]LCAIINFRSSEEWGWNDIHCH VPQKS CLIC6 c.892C>G p.Q298 EGPAGDSMDAEGPAGRARRVSGEPQ[p. EPQESGDGSL ACC E p.Q298E]ESGDGSLSPQAEAIEVAAGES AGRSP CLIP1 c.3052_3053 p.S101 AAKKHEEEKKELERKLSDLEKKMET[p.S KMETKPQPV,METKPQPVS,ETKPQPVSGA,KKMETKPQPV BLCA,KIRP insA 8fs 1018fs]KPQPVSGAESQV* CLK4 c.203G>T p.R68L CKPHHQFKESDCHYLEARSLNERDY[p. RSLNERDYL,LDRRYVDEY,RDYLDRRYV,YLDRRYVDEY,SLN LUAD R68L]LDRRYVDEYRNDYCEGYVPRHYH ERDYLDR,NERDYLDRRY RDI CLN3 c.616G>A p.G206 ISWWSSGTGGAGLLGALSYLGLTQA[p. YLGLTQASL,SLSPQQTLL,ASLSPQQTL,SYLGLTQASL,LSYLG LUSC S G206S]SLSPQQTLLSMLGIPALLLASYFL LTQAS,ASLSPQQTLL LL CLSTN c.1844C>T p.T615 LEGEDLGELDKAMQHISYLNSRQFP[p.T YLNSRQFPM,RQFPMPGIR,QFPMPGIRR,FPMPGIRRL,MP STAD 1 M 615M]MPGIRRLKITSTIKCFNEATCISVP GIRRLKI,RQFPMPGIRR,SYLNSRQFPM,NSRQFPMPGI P CLSTN c.2276C>T p.P759 YSIYGVGSMSRYEQVLHHIRYRNWR[p. HIRYRNWRL,RYRNWRLAS,RLASLEARR,YRNWRLASL,LAS HNSC 2 L P759L]LASLEARRFRIKCSELNGRYTSNE LEARRF,RYRNWRLASL,HIRYRNWRLA,RLASLEARRF,NWR FN LASLEAR,LASLEARRFR,HHIRYRNWRL,RNWRLASLEA CLUL1 c.1387G>C p.G463 SELANQAPETEIIFNSIQVVPRIHE[p.G4 RIHERNISK,QVVPRIFIER,VPRIHERNI,RNISKQDETM KIRC R 63R]RNISKQDETMMTDLSILPSSNFTLK I CMA1 c.242T>A p.I81K IRRNFVLTAAHCAGRSITVTLGAHN[p.I TVTLGAHNK,ITVTLGAHNK,KTEEEDTWQK CLL 81K]KTEEEDTWQKLEVIKQFRHPKYNT ST CMAS c.329G>A p.R110 FQSVWVSTDHDEIENVAKQFGAQVH[ HQRSSEVSK,QFGAQVHQR,KQFGAQVHQ,AQVHQRSSEV, CRC Q p.R110Q]QRSSEVSKDSSTSLDAIIEFLN KQFGAQVHQR YHNE CMIP c.688G>A p.A230 EIVSKLLSENTNLTTQEHENIIVAI[p.A23 IIVAITPLL,NIIVAITPL,HENIIVAIT,NIIVAITPLL CLL T 0T]TPLLENNHPPPDLCEFFCKHCRERPR CMT c.77G>C p.S26T MEEPQRARSHTVTTTASSFAENFST[p.S STTSSSFAY,TSSSFAYDR,FSTTSSSFA,AENFSTTSS, TGCT M8 26T]TSSSFAYDREFLRTLPGFLIVAEIVL NFSTTSSSF,FSTTSSSFAY,TTSSSFAYDR,ENFSTTSSSF, SSFAENFSTT,AENFSTTSSS CNBD c.1187T>C p.L396 RSIIGFVKLRSNKVKRSQKLVYMGK[p.L KLVYMGKPK,LVYMGKPKEK,MGKPKEKESF STAD 1 P 396P]PKEKESFGEISVLLQVPFTCTIITKK CNGA c.1529A>C p.K510 AEIALQEATESRLRGLDQQLDDLQT[p.K TFARLLAEL,QLDDLQTTF,LQTTFARLL,QLDDLQTTFA,TTFA STAD 4 T 510T]TFARLLAELESSALKIAYRIERLEW RLLAEL,QQLDDLQTTF,LQTTFARLLA Q CNKS c.746C>T p.P249 SEGLGMYIKSTYDGLHVITGTTENS[p.P SLADRCKKI,NSLADRCKK TGCT R2 L 249L]LADRCKKIHAGDEVIQVNHQTVV GWQ CNOT c.58G>A p.E20K MADKRKLQGEIDRCLKKVS[p.E20K]KG CLKKVSKGV,KVSKGVEQF,KKVSKGVEQF PRAD 3 VEQFEDIWQKLHNAANANQKEKYE CNOT c.744de|T p.S248fs QEILSCNADIVSLQEVETEQYYSFF[p.S2 TEQYYSFFW STAD 6 48fs]W* CNRIP c.304C>T p.R102 EPDGDRWYTGTYDTEGVTPTKSGE[p. EWQPIQITM,TKSGEWQPI,GEWQPIQIT,WQPIQITMPF,G CRC 1 W R102W]WQPIQITMPFTDIGTFETVWQ EWQPIQITM VKFYN CNTFR c.754G>T p.D252 QTPSTWPDPESFPLKFFLRYRPLIL[p.D2 LILYQWQHV,YRPLILYQW,LYQWQHVEL,RYRPLILYQ,LRYR LUAD Y 52Y]YQWQHVELSDGTAHTITDAYAGK PLILY,YQWQHVELS,ILYQWQHVEL,PLILYQWQHV,FLRYR EYI PLILY,RYRPLILYQW,YQWQHVELSD CNTN c.1136C>T p.S379 LEIPNVQLDDAGIYECRAENSRGKN[p.S NSRGKNFFR,FFRGQLQVY,AENSRGKNF,GKNFFRGQL,RG SKCM 5 F 379F]FFRGQLQVYTYPHWVEKLNDTQ KNFFRGQL,KNFFRGQLQV,NFFRGQLQVY,ENSRGKNFFR, LDSG RAENSRGKNF,AENSRGKNFF CNTN c.533C>A p.T178 IDGTFIISNPSEAKDSGHYQCLATN[p.T1 YQCLATNNV,LATNNVGSI,CLATNNVGSI,HYQCLATNNV,Y LUSC 5 N 78N]NVGSILSREATLQFAYLGNFSGRTR QCLATNNVG,LATNNVGSIL S CNTN c.2420G>T p.R807 NNEGEGSLSTVTIVYSGEDEPQLAP[p.R QLQPMGTSL,PMGTSLQSF,APMGTSLQSF,GEDEPQLAPM, LUAD 6 M 807M]MGTSLQSFSASEMEVSWNAIA PQLAPMGTSL WNRNT CNTN c.3086G>T p.S102 EPGTWMRYNLQSALRSAAREFSHML[p. FSHMLIRPV,MLIRPVPGY,REFSHMLIR,AAREFSHMLI,HM PRAD AP1 9I S1029I]IRPVPGYEPGYIPGYDTPGYVP LIRPVPGY,EFSHMLIRPV,REFSHMLIRP GYHG CNTN c.1185C>A p.F395 EPYTVPVFFNATSYLEVPGRLNQDL[p.F RLNQDLLSV,LLSVSFQFR,DLLSVSFQF,NQDLLSVSF,LLSVSF LUAD AP2 L 395L]LSVSFQFRTWNPNGLLVFSHFAD QFRT,DLLSVSFQFR,LNQDLLSVSF,QDLLSVSFQF NLG CNTN c.1307A>C p.Y436 LFSELQLISGGILLFLSDGKLKSNL[p.Y43 KSNLSQPGK,KLKSNLSQPG,KSNLSQPGKL KIRC AP4 S 6S]SQPGKLPSDITAGVELNDGQWHSV SL CNTN c.34A>T p.I12F MLLFYLLVVLS[p.I12F]FDSTKASALTNP VLSFDSTKA,VVLSFDSTK,FYLLVVLSF,FDSTKASAL,LVVLSF CLL AP4 NVALFLLADDCDDP DSTK,LFYLLVVLSF,LSFDSTKASA CNTRL c.553C>T p.P185 SKIEGIENMCNLQKLNLAGNEIEHI[p.P1 HISVWLGKK,SVWLGKKLK,EIEHISVWL,NEIEHISVW,ISVW CESC S 85S]SVWLGKKLKSLRVLNLKGNKISSLQ LGKKL,ISVWLGKKLK,NEIEHISVWL D CNTR c.2759_2760 p.R920 PKTEKPPARKKSGHPAPSSMRSRGG[p. TLSPLCSLI,SMRSRGGSL,MSPPTLSPL,RSRGGSLEM,SPLCS STAD OB insG fs R920fs]SLEMSPPTLSPLCSLIVVILINAH* LIVV,SLEMSPPTL,LEMSPPTLS,TLSPLCSLIV,SLVVILINA, EMSPPTLSPL,SSMRSRGGSL,SMRSRGGSLE,RSRGGSLEMS, SPLCSLIVVI,MRSRGGSLEM,GSLEMSPPTL,LEMSPPTLSP COBLL c.2196A>C p.K732 DPLTVKDPICAHGNDDLLPPVDRID[p.K IDNNSTASY,RIDNNSTASY,IDNNSTASYL CRC 1 N 732N]NNSTASYLKNYPLYRQDYNPKPK PSN COG5 c.1850A>G p.H617 TKVVSSQSSFPLAAEQTIISALKAI[p.H61 ALKAIRALM,AIRALMENA,IISALKAIR,SALKAIRAL, TGCT R 7R]RALMENAVQPLLTSVGDAIEAIIITM AIRALMENAV,SALKAIRALM,TIISALKAIR,ISALKAIRAL COL14 c.3245G>T p.R108 STVGALNKIGTDGTQVAMVQFTDDP[p. FTDDPITEF,ITEFKLNAY,MVQFTDDPI,VQFTDDPIT,FTDDP CRC A1 2I R1082I]ITEFKLNAYKTKETLLDAIKHISY ITEFK,AMVQFTDDPI,ITEFKLNAYK,QFTDDPITEF KG COL15 c.2123A>G p.K708 ARGPNGSVGEKGDPGNRGLPGPPGK[p. RGQAGPPGVM TGCT A1 R K708R]RGQAGPPGVMGPPGPPGPP GPPGPGC COL18 c.2652de|C p.G884 DRGSRGEKGDPGKDGVGQPGLPGPP[p. DLWSTCRSR KIRP A1 fs G884fs]DPRDLWSTCRSRTDPS* COL19 c.1613C>A p.P538 GPPGLIGSPGLKGQQGSAGSMGPRG[p. GPRGQPGDV LUAD A1 Q P538Q]QPGDVGLPGEHGIPGKQGIKG EKGDP COL4 c.16480A p.L550 GPAGAPGLVGPLGPSGPKGKKGEPI[p. KGKKGEPII,KKGEPIISTI,EPIISTIQGM CRC A6 I L550I]ISTIQGMPGDRGDSGSQGFRGV IGEP COL5 c.1546G>T p.G516 QGPIGPPGEEGKRGPRGDPGTVGPP[p. GTVGPPWPV,DPGTVGPPW LUAD A2 W G516W]WPVGERGAPGNRGFPGSDGL PGPKGA COL5 c.1834G>T p.G612 LGPLGAPGEDGRPGPPGSIGIRGQP[p. WSMGLPGPK,SIGIRGQPW,RGQPWSMGL,QPWSMGLPG, LUAD A2 W G612W]WSMGLPGPKGSSGDPGKPGE GSIGIRGQPW,IGIRGQPWSM AGNAGV COL6 c.7133C>A p.A237 GQKGDPGYPGPAGPKGNRGDSIDQC DSIDQCDLI TGCT A3 8D [p.A2378D]DLIQSIKDKCPCCYGPLECPV FPTEL C0L6 c.8374G>A p.D279 YFFVVLGIGRKVNIKEVYTFASEPN[p.D2 NVFFKLVDK,FASEPNNVF,ASEPNNVFF,EPNNVFFKL,YTFA CRC A3 2N 792N]NVFFKLVDKSTELNEEPLMRFGR SEPNNV,ASEPNNVFFK,TFASEPNNVF,FASEPNNVFF,EPN LLP NVFFKLV,SEPNNVFFKL COL6 c.6671C>T p.T222 QEDFLGGNGFIGQELNSGRESPFVK[p. KMEDNGSDY,MEDNGSDYL,KMEDNGSDYL,SGRESPFVK GBM A5 4M T2224M]MEDNGSDYLVYLPSQMFEP M,VKMEDNGSDY,MEDNGSDYLV QKLMINY COL9 c.632C>A p.P211 GVERSSATLFVDCNRIESLPIKPRG[p.P2 QIDIDGFAV,GQIDIDGFA,LPIKPRGQI,GQIDIDGFAV LUAD A1 Q 11Q]QIDIDGFAVLGKLADNPQVSVPFE LQ COL9 c.848de|C p.P283 RITPSQTTDERGPPGEQGPPGPPGP[p. FQASMASTV,SMASTVTEV,ELQASLAHL,LQASLAHLA,VLR STAD A1 fs P283fs]LEFQASMASTVTEVLRAPRAPR APRAPR,ASLAHLALM,VTEVLRAPR,MASTVTEVL,ESQELQ VLQVNRESQELQASLAHLALMD* ASL,GPLEFQASM,LEFQASMAS,RESQELQAS,QELQASLAH, QASLAHLAL,TEVLRAPRA,ASMASTVTEV,SMASTVTEVL,L QASLAHLAL,FQASMASTVT,VLRAPRAPRV,ELQASLAHLA, MASTVTEVLR,TVTEVLRAPR,EVLRAPRAPR,ESQELQASLA, APRAPRVLQV,LEFQASMAST,LRAPRAPRVL,LQVNRESQE L,RESQELQASL,SQELQASLAH,QELQASLAHL,QASLAHLAL M COPB c.1273C>T p.R425 NVIPVLMEFLSDNNEAAAADVLEFV[p. EFVCEAIQR,DVLEFVCEA,FVCEAIQRF,EFVCEAIQRF,DVLE CRC 1 C R425C]CEAIQRFDNLRMLIVEKMLEVF FVCEAI,CEAIQRFDNL HAIK COQ2 c.196G>T p.V66L SFALARAAGAPHGGDLQPPACPEPR[p. RWRQLSLSA,CPEPRWRQL,EPRWRQLSL,WRQLSLSAA,R ACC V66L]WRQLSLSAAAVVDSAPRPLQPYL WRQLSLSAA,WRQLSLSAAA,QPPACPEPRW RLM CORO c.1576T>A p.*526 LTQREVQAKQLELEIKNLRMGSEQL[p.* QLRAETSAL,TLRDTTRLH,ETSALLTLR,LLTLRDTTR,DTTRLH CRC 2A R 526R]RAETSALLTLRDTTRLHGEV* GEV,LRAETSALL,AETSALLTL,SEQLRAETS,QLRAETSALL, LLTLRDTTRL,NLRMGSEQLR,SEQLRAETSA,EQLRAETSAL,RA ETSALLTL COX1 c.256C>A p.L86I PSKAAERVVGRWLLVCSGTVAGAVI[p. VIIGGVTRL CRC 5 L86I]IGGVTRLTESGLSMVDWHLIKEM KPP COX6 c.23C>T p.S8L MAVVGVS[p.S8L]LVSRLLGRSRPQLGR MAVVGVSLV,SLVSRLLGR,AVVGVSLVSR,VSLVSRLLGR,LV BLCA A1 PMSSGAHGEEG SRLLGRSR CPAM c.2352de|C p.P784 TDEAVPAFQPHTGSLVAVAPSRHPP[p. IVSTSVTHL,STSVTHLVR,REKGLSSPK,VSTSVTHLV,SPKHG STAD D8 fs P784fs]EQRREKGLSSPKHGFGIVSTSVT FGIV,GLSSPKHGF,IVSTSVTHLV,GIVSTSVTHL,VSTSVTHLV HLVRGHSV* R,VTHLVRGHSV,HGFGIVSTSV,KGLSSPKFGF,FGIVSTSVT H CPE c.869C>A p.P290 SAHEYSSSPDDAIFQSLARAYSSFN[p.P2 RAYSSFNQA,AYSSFNQAM,RAYSSFNQAM LUAD Q 90Q]QAMSDPNRPPCRKNDDDSSFVD GTTN CPNE c.381G>T p.Q127 SKSPNLSKHDFLGQVFCTLGEIVGS[p.Q GSHGSRLEK,EIVGSHGSR,GEIVGSHGS,VGSHGSRLEK,EIV LUAD 8 H 127H]HGSRLEKPIVGIPGKKCGTIILTAE GSHGSRL E CPS1 c.2564C>A p.T855 TPRLPMNKEWPSNLDLRKELSEPSS[p.T SSKRIYAIA,SKRIYAIAK,ELSEPSSKR,SEPSSKRIY, LUSC K 855K]KRIYAIAKAIDDNMSLDEIEKLTYI LSEPSSKRIY,SSKRIYAIAK,EPSSKRIYAI,KRIYAIAKAI D CPSF4 c.656C>A p.P219 NPPLQRSSSLIQLTSQNSSPNQQRT[p.P RTQQVIGVM,NQQRTQQVI,SPNQQRTQQV,QQRTQQVIG LUAD Q 219Q]QQVIGVMQSQNSSAGNRGPRP V,QRTQQVIGVM LEQVT CR1L c.237de|A p.L79 PIGTYLNYECRPGYSGRPFSIICLK[p.L79 CLKTQSGQV,QVLRTSANV,RTSANVNHV,KTQSGQVLR,TS STAD fs fs]TQSGQVLRTSANVNHWILQIL* ANVNHVV,LKTQSGQVL,SANVNHVVI,ANVNHVVIL,,GQVL RTSANV,RTSANVNHVV,TSANVNHVVI,NVNHVVILQI,CLK TQSGQVL,SANVNHVVIL CR2 c.618de|C p.V206 ESGYLLVGEKIINCLSSGKWSAVPP[p.V WSAVPPHVK,KWSAVPPHV,HVKRHAVNL,SAVPPHVKR,P STAD fs 206fs]HVKRHAVNL* PHVKRHAV,GKWSAVPPH,SGKWSAVPPH,KWSAVPPHVK, WSAVPPHVKR,VPPHVKRHAV,GKWSAVPPHV CRB1 c.1883de|T p.L628 SICAFQNSFLGGLPVGMTSNGVALL[p.L SIICHPHLR,SIICHPHLRL,TSIICHPHLR,MTSNGVALLT, HNSC fs 628fs]TSIICHPHLRL* LTSIICHPHL CRB1 c.1888T>G p.F630 ICAFQNSFLGGLPVGMTSNGVALLN[p. NGVALLNVY,VALLNVYNM,LLNVYNMPST,VYNMPSTPSF, STAD V F630V]VYNMPSTPSFVGCLQDIKIDWN SNGVALLNVY,TSNGVALLNV HITL CRB2 c.3329C>T p.T111 GWEGPRCEAHVDPCHSAPCARGRCH[p. RGRCHMHPD,CHMHPDGRF,RGRCHMHPDG,APCARGRC ACC 0M T1110M]MHPDGRFECRCPPGFGGP HM,RCHMHPDGRF,HMHPDGRFEC RCRLPVPS CREBB c.4303G>C p.D143 FGMHVQEYGSDCPPPNTRRVYISYL[p. YLHSIHFFR,HSIHFFRPR,VYISYLHSI,ISYLHSIHF,SYLHS BLCA P 5H D1435H]HSIHFFRPRCLRTAVYHEILIGY IHFF,RVYISYLHS,YISYLHSIH,RVYISYLHSI,SYLHSIHF LEY FR,YISYLHSIHF,ISYLHSIHFF CREBB c.4337G>A p.R144 CPPPNTRRVYISYLDSIHFFRPRCL[p.R1 HFFRPRCLH,HTAVYHEIL,RPRCLHTAV,FFRPRCLHT,CLHT DLBCL P 6H 446H]HTAVYHEILIGYLEYVKKLGYVTG AVYHEI,FFRPRCLHTA,RPRCLHTAVY,HTAVYHEILI HI CREBB c.6281C>T p.P209 DLLRTLKSPSSPQQQQQVLNILKSN[p.P VLNILKSNL,ILKSNLQLM,NLQLMAAFI,LQLMAAFIK,KSNL UCEC P 4L 2094L]LQLMAAFIKQRTAKYVANQPG QLMAA,SNLQLMAAF,LKSNLQLMA,ILKSNLQLMA,NLQL MQPQP MAAFIK,KSNLQLMAAF,LKSNLQLMAA CRIPA c.142_143i p.M48 PACSCAHVECPPAHTCRCGVPACSH[p. SMWSAHLLM,HLLMCPCGV,WSARLLTHV,HVSMWSAHL, BLCA K nsCG fs M48fs]TCPCGVPACSHVPMWSARLLT RLLTHVSMW,LTHVSMWSA,HTCQRGVPA,MWSARLLTH, HVSMWSAHLLMCPCGVPTCSHVPM TWSARLLTR,VPTCSHVPM,VPACSRAHV,VPTWSARLL,AR WSATCSHTCPCGVPACSRAHVECPPAH LLTHVSM,THVSMWSAH,VSMWSAHLL,LMCPCGVPT,SH TCRCGVPACSHVPMRSARLLTRAHAEC VPMWSAT,LLTHVSMWSA,SMWSAHLLMC,LLMCPCGVP PPAHTCPCGVPACSHVPTWSARLLTRA T,HVSMWSAHLL,GVPACSRAHV,SARLLTHVSM,PTWSAR HVECPPAHTCQRGVPA* LLTR,HVPTWSARLL,ARLLTHVSMW,LTHVSMWSAH,THV SMWSAHL,VSMWSAHLLM,VPTCSHVPMW,VPMWSATC SH CRIPA c.427T>C p.C143 SHVPMRSARLLTRAHAECPPAHTCP[p. HTCPRGVPA,CPPAHTCPR,RGVPACSHV ACC K R C143R]RGVPACSHVPMRSARLLTRAD VECPP CRIPA c.520T>C p.C174 SHVPMRSARLLTRADVECPPAHTCP[p. HTCPRGVPA,CPPAHTCPR,RGVPACSHV ACC K R C174R]RGVPACSHVPTWSARLITRAHV ECSP CRIPA c.538_568 p.S180 LTRADVECPPAHTCPCGVPACSHVP[p. FLSCRPSQT,TLLPYILLM,LLPYILLMV,CLPAHTCPC,HMCRC LUAD K de|TCA fs S180fs]MWSARLLTRADVECLPAHTCP GVPA,WSARLLTHV,GSVGFLSCR,VFACSHVPM,RLLTHVP CACGT CGVFACSHVPMRSARLLTRADAECPPA MW,PWHGGSVGF,PYILLMVAF,HTCPCGVFA,SARLLTRAI, GCCAA HTCPCGVPACSRADVECPPAHTCPCGV LTRAHVECL,RAHVECLPA,MWSARLLTH,RPSQTLLPY,FAC CGTGG PACSRADVGCPPAHMCRCGVPACSHV SHVPMR,IWSARLLTR,DVECPPAFV,HVPIWSARL,QTLLPYI AGTGC PMWSARLLTRADVECPPAHVPIWSARL LL,VPACSRADV,VPIWSARLL,LPAHTRAHV,AHTCPCGVF,R LTRAIVECPPAHTHADVECPPAHTCPCG AIVECPPA,ARLLTHVPM,AHVECLPAH,LSCRPSQTL,SQTLL VPACSHVPMWSARLLTHVPMWSARLL PYIL,LPYILLMVA,CPPAHVPIW,CPPAHTKPW,LLTRAHVEC TRAHVECLPAHTRAHVECPPAHTKPW L,CLPAHTRAHV,FLSCRPSQTL,TLLPYILLMV,LLPYILLMVA, HGGSVGFLSCRPSQTLLPYILLMVAF* LLTRADVECL,HVECPPAHTK,GVFACSHVPM,SARLLTRAD A,SARLLTRAIV,SARLLTHVPM,HTKPWHGGSV,VFACSHVP MR,PAHVPIWSAR,PIWSARLLTR,HVECLPAHTR,HVPIWS ARLL,WSARLLTRAI,KPWHGGSVGF,RPSQTLLPYI,LPYILLM VAF,SRADVGCPPA,ADVGCPPAHM,AHMCRCGVPA,VECP PAHVPI,AHVPIWSARL,RAIVECPPAH,ARLLTHVPMW,RA HVECLPAH,LSCRPSQTLL,CRPSQTLLPY,SQTLLPYILL,VECL PAHTRA,VECPPAHTHA,LPAHTCPCGV,CPPAHTHADV CRIPA c.568A>C p.I190 ECPPAHTCPCGVPACSHVPTWSARL[p. TWSARLLTR,VPTWSARLL,PTWSARLLTR,HVPTWSARLL ACC K L I190L]LTRAHVECSPAHTCRCGVPACSH VPM CRISP c.664C>T p.R222 PKAVYLVCNYSPKGNWWGHAPYKHG[p. APYKHGWPC,YKHGWPCSA,WPCSACPPS,WPCSACPPSF, BRCA LD1 W R222W]WPCSACPPSFGGGCRENLC YKHGWPCSAC YKEGSDR CROC c.1063G>C p.A355 RTSRAVQEAGLGLSTGLRLAESRAE[p.A EPALEKQAL,AESRAEPAL,RLAESRAEPA,ESRAEPALEK,AEP KIRP C P 355P]PALEKQALLQAQLEEQLRDKVLR ALEKQAL EKD CROT c.1740G>T p.Q580 DPLFSKSGGGGNFVLSTSLVGYLRV[p.Q YLRVHGVVV,GYLRVHGVV,RVHGVVVPM,RVHGVVVPMV, LUAD H 580H]HGVVVPMVHNGYGFFYHIRDDR LVGYLRVHGV,GYLRVHGVVV,LRVHGVVVPM FVVA CROT c.96de|A p.L32 TEERTFQYQDSLPSLPVPSLEESLK[p.L3 LEESLKNTL STAD fs 2fs]NTLNQSPEHATR* CRTC3 c.1088C>T p.S363 NKTVLSSSLNNHPQTSVPNASALHP[p.S ASALHPLLR,ALHPLLRLF,NASALHPLL,HPLLRLFSL,SALHPL LUAD L 363L]LLRLFSLSNPSLSTTNLSGPSRRRQ LRLF,NASALHPLLR,VPNASALHPL P CRYG c.427A>G p.R143 HLTEIHSLNVLEGSWILYEMPNYRG[p.R NYRGGQYLL,MPNYRGGQY,YEMPNYRGG,EMPNYRGGQ TGCT B G 143G]GQYLLRPGEYRRFLDWGAPNAK Y,GQYLLRPGEY,NYRGGQYLLR,MPNYRGGQYL VGSL CRYG c.476de|G p.G159 YEMPNYRGRQYLLRPGDYRRYHDWG[p. RYHDWGVQM,GVQMPKSAL,RRYHDWGVQM,WGVQM STAD D fs G159fs]VQMPKSAL* PKSAL CRYM c.943T>A p.*315 FKSLGMAVEDTVAAKLIYDSWSSGK[p. SWSSGKKNK CLL K *315K]KNKGT* CSDE1 c.658C>T p.R220 NVQLETGDKINFVIDNNKHTGAVSA[p. SACNIMLLK,GAVSACNIM,AVSACNIMLL,VSACNIMLLK,S UCEC C R220C]CNIMLLKKKQARCQGVVCAMK ACNIMLLKK,HTGAVSACNI EAFGF CSF2R c.892G>A p.G298 SFGLFYKPSPDAGEEECSPVLREGL[p.G VLREGLSSL,EGLSSLHTR,REGLSSLHT GBM B S 298S]SSLHTRHHCQIPVPDPATHGQYI VSV CSF3R c.1404de|C p.P468 SLWVGWEPPNPWPQGYVIEWGLGPP[p. ATRPGGWNR,RAIATRPGG,EWGLGPPAR,IEWGLGPPA,A STAD fs P468fs]ARAIATRPGGWNRMGEPRG TRPGGWNRM,IATRPGGWNR,RAIATRPGGW,IEWGLGPP FC* AR CSGAL c.1086G>T p.L362 VSLNEEFNRGRGLNVGARAWDKGEV[p. FMFFCDVDI,EVFMFFCDV,RAWDKGEVF,GEVFMFFCD,A ACC,KIRP, NACT F L362F]FMFFCDVDIYFSAEFLNSCRL WDKGEVFMF,VFMFFCDVDI,RAWDKGEVFM,FMFFCDV TGCT 2 NAEPG DIY,ARAWDKGEVF,GEVFMFFCDV CSHL1 c.350G>A p.R117 SSNMEETQQKSNLELLHISLLLIES[p.R1 SLLLIESQL,LIESQLEPV,SQLEPVRFL,QLEPVRFLR,LLI CESC Q 17Q]QLEPVRFLRSTFTNNLVYDTSDSD ESQLEPV,SQLEPVRFLR,ISLLLIESQL,IESQLEPVRF DY CSMD c.5564C>A p.P185 PTCVVPCGGNLTERRGTILSPGFPE[p.P QYLNSLNCV,FPEQYLNSL,GFPEQYLNSL,QYLNSLNCVW,IL LUAD 2 5Q 1855Q]QYLNSLNCVWKIVVPEGAGIQI SPGFPEQY,EQYLNSLNCV QVVS CSMD c.2071C>A p.Q691 DPGTPLYGIREGDGFSNRDVLRFEC[p.Q LRFECKFGF,FECKFGFEL,RFECKFGFEL,VLRFECKFGF, LUSC 3 K 691K]KFGFELIGEKSIVCQENNQWSAN RDVLRFECKF,FECKFGFELI IPI CSMD c.2854C>T p.H952 AEPGHSIKITFERFQTELNYDVLEV[p.H9 LNYDVLEVY,EVYDGPNLL,LEVYDGPNL,ELNYDVLEVY,EVY CESC 3 Y 52Y]YDGPNLLSPLLGSYNGTQVPQFLFS DGPNLLS,LEVYDGPNLL,YDGPNLLSPL S CSMD c.3281C>A p.T109 GDVRGPSGTILSPGYPEFYPNSLNC[p.T NSLNCKWTV,YPNSLNCKW,SLNCKWTVDV,FYPNSLNCK LUSC 3 4K 1094K]KWTVDVTHGKGVQFNFHTFHL W,KWTVDVTHGK,EFYPNSLNCK EDHHD CSMD c.511G>A p.E171 STKSVFSLRLTSDFAVSAHGFKVYY[p.E1 AHGFKVYYK,SAHGFKVYYK,HGFKVYYKEL GBM 3 K 71K]KELQSSSCGNPGVPPKGVLYGTRF DV CSMD c.522G>T p.Q174 SVFSLRLTSDFAVSAHGFKVYYEEL[p.Q YEELHSSSC,HSSSCGNPGV LUAD 3 H 174H]HSSSCGNPGVPPKGVLYGTRFDV GDK CSMD c.7149_ p.F238 LESVYSTSNQILIKFHSDFTTSGFF[p. FTTSGFFCA,AQLSRLSTK,GFFCAQLSR,LSRLSTKGV,QLSRL LIHC 3 7150insT 3fs F2383fs]CAQLSRLSTKGVPTSTTCAQC* STKGV,SGFFCAQLSR,CAQLSRLSTK,TTSGFFCAQL,AQLSRL STKG CSMD c.8179C>A p.P272 LEHGRWRIVNGSHYEYKTKVVFSCD[p. VVFSCDTGY,VVFSCDTGYH,KTKVVFSCDT,KVVFSCDTGY,F LUAD 3 7T P2727T]TGYHGLGPASIECLPNGTWS SCDTGYHGL,DTGYHGLGPA WRNERP CSMD c.8429C>A p.T281 CDLGFMLVGSAVRECLSSGLWSESE[p. SESENRCLA,SENRCLAGH LUAD 3 0N T2810N]NRCLAGHCGIPELIVNGQVIG ENYGY CSPG5 c.355G>A p.D119 AVTGTAWLEADSPGLGGVTAEAGSG[p. VTAEAGSGNA,AEAGSGNAQA BLCA N D119N]NAQALPATLQAPHEVLGQSI MPPAIP CT47B c.702728d p.234_ DLAEMAREPAEEAADEKPPEEAAEE[p. EEAAEEPAA,AEEPAAEEPT BRCA 1 e|GAAGCTC 243EKL 234_243EKLTEEATEE>E]PAAEEPTSEE ACAGAGGA TEEATE AVAPEEVTKSQPEKWDEEAQDAAGEE GGCCACAG E>E EKEQEKEKDVENKVKN AGGA CTAG c.1091C>T p.A364 IIQISFVDKTKFFITFHIKNIQTQQ[p.A3 VSLQSENIY,NLQTQQVSL,HIKNLQTQQV,QVSLQSENIY,K KIRP E15P V 64V]VSLQSENIYFESENQKLQQKLKIMT NLQTQQVSL,QQVSLQSENI,VSLQSENIYF E CTCF c.604_605 p.K202 EQGELPPQEDPSWQKDPDYQPPAKK[p. RANCVIQRR,KPKRANCVI,KQRKPKRANC,RANCVIQRRA STAD insAA fs K202fs]KQRKPKRANCVIQRRAKM* CTCF c.604de|A p.K202 EQGELPPQEDPSWQKDPDYQPPAKK[p. RANCVIQRR,KPKRANCVI,KQRKPKRANC,RANCVIQRRA STAD fs K202fs]QRKPKRANCVIQRRAKM* CTCFL c.1267G>A p.E423 YECHICHTRFTQSGTMKIHILQKHG[p.E ILQKHGKNV,KHGKNVPKY,KIHILQKHGK,LQKHGKNVPK,Q CRC K 423K]KNVPKYQCPHCATIIARKSDLRVH KHGKNVPKY MR CTDN c.376G>A p.E126 KHPVRFFVHKRPHVDFFLEVVSQWY[p. KLVVFTASM,VVSQWYKLV,SQWYKLVVF,WYKLVVFTA,EV CRC EP1 K E126K]KLVVFTASMEIYGSAVADKLDN VSQWYKL,YKLVVFTAS,FLEVVSQWYK,VSQWYKLVVF,EV SRSI VSQWYKLV,YKLVVFTASM,LEVVSQWYKL,SQWYKLVVFT CTNN c.2567_ p.K856 IIRIQSPAGPRHPVVMWRMKAPAKK[p. RMKAPAKKNP STAD A3 2568insAA fs K856fs]NP* CTNN c.1004A>T p.K335 ESKLIILASGGPQALVNIMRTYTYE[p.K3 IMRTYTYEI,YTYEILLWT,ILLWTTSRV,TYTYEILLW,TYE LIHC B1 I 35I]ILLWTTSRVLKVLSVCSSNKPAIVEA ILLWTT,RTYTYEILL,EILLWTTSR,MRTYTYEIL,YEILLW TTS,NIMRTYTYEI,YTYEILLWTT,ILLWTTSRVL,IMRTY TYEIL,RTYTYEILLW,EILLWTTSRV,MRTYTYEILL,YEI LLWTTSR CTNN c.100G>A p.G34R ELDMAMEPDRKAAVSHWQQQSYLDS[p. QQSYLDSRI,RIHSGATTT,YLDSRIHSGA,RIHSGATTTA,QQ UCEC B1 G34R]RIHSGATTTAPSLSGKGNPEEE QSYLDSRI,QQSYLDSRIH DVDT CTNN c.101G>T p.G34V ELDMAMEPDRKAAVSHWQQQSYLDS[p. QQQSYLDSV,YLDSVIHSG,QQSYLDSVI,WQQQSYLDSV,YL LIHC B1 G34V]VIHSGATTTAPSLSGKGNPEEE DSVIHSGA,VIHSGATTTA,QQQSYLDSVI,QQSYLDSVIH DVDT CTNN c.107A>C p.H36P DMAMEPDRKAAVSHWQQQSYLDSGI[p. YLDSGIPSG,IPSGATTTA,YLDSGIPSGA LIHC B1 H36P]PSGATTTAPSLSGKGNPEEEDV DTSQ CTNN c.109T>G p.S37A MAMEPDRKAAVSHWQQQSYLDSGIH[p. YLDSGIHAG,IHAGATTTA,YLDSGIHAGA,GIHAGATTTA,AG UCEC B1 S37A]AGATTTAPSLSGKGNPEEEDV ATTTAPSL DTSQV CTNN c.110C>G p.S37C MAMEPDRKAAVSHWQQQSYLDSGIH[p. YLDSGIHCGA,GIHCGATTTA UCEC B1 S37C]CGATTTAPSLSGKGNPEEEDVD TSQV CTNN c.110C>T p.S37F MAMEPDRKAAVSHWQQQSYLDSGIH YLDSGIHFG,SYLDSGIHF,IHFGATTTA,YLDSGIHFGA, LUAD,UCEC B1 [p.S37F]FGATTTAPSLSGKGNPEEEDVD GIHFGATTTA,QSYLDSGIHF,IHFGATTTAP,FGATTTAPSL TSQV CTNN c.1161T>A p.N387 GMQALGLHLTDPSQRLVQNCLWTLR[p. VQNCLWTLRK LIHC B1 K p.N387K]KLSDAATKQEGMEGLLGTLV QLLGSD CTNN c.121A>G p.T41A PDRKAAVSHWQQQSYLDSGIHSGAT[p. ATAPSLSGK,GATATAPSL,GIHSGATATA,TATAPSLSGK,SG PRAD B1 T41A]ATAPSLSGKGNPEEEDVDTSQVL ATATAPSL YEW CTNN c.122C>T p.T41I PDRKAAVSHWQQQSYLDSGIHSGAT[p. ITAPSLSGK,SGIHSGATI,TITAPSLSGK,SGATITAPSL UCEC B1 T41I]ITAPSLSGKGNPEEEDVDTSQVLY EW CTNN c.133T>C p.S45P AAVSHWQQQSYLDSGIHSGATTTAP[p. TTAPPLSGK,GATTTAPPL,TTAPPLSGK,SGATTTAPPL ACC,LIHC B1 S45P]PLSGKGNPEEEDVDTSQVLYEW EQGF CTNN c.94G>A p.D32N LMELDMAMEPDRKAAVSHWQQQSYL YLNSGIHSG,QQSYLNSGI,WQQQSYLNS,QQQSYLNSG,YL LIHC,UCEC B1 [p.D32N]NSGIHSGATTTAPSLSGKGNP NSGIHSGA,QQQSYLNSGI,WQQQSYLNSG,QQSYLNSGIH EEEDV CTNN c.94G>T p.D32Y LMELDMAMEPDRKAAVSHWQQQSYL YLYSGIHSG,QQSYLYSGI,HWQQQSYLY,WQQQSYLYS,QQ UCEC B1 [p.D32Y]YSGIHSGATTTAPSLSGKGNPE QSYLYSG,QSYLYSGIH,YLYSGIHSGA,QQQSYLYSGI,SHWQ EEDV QQSYLY,WQQQSYLYSG,QQSYLYSGIH CTNN c.95A>G p.D32G LMELDMAMEPDRKAAVSHWQQQSYL YLGSGIHSG,WQQQSYLGS,QQQSYLGSG,QQSYLGSGI,QS CESC,LIHC B1 [p.D32G]GSGIHSGATTTAPSLSGKGNP YLGSGIH,YLGSGIHSGA,WQQQSYLGSG,QQQSYLGSGI,Q EEEDV QSYLGSGIH CTNN c.95A>T p.D32V LMELDMAMEPDRKAAVSHWQQQSYL QQSYLVSGI,YLVSGIHSG,LVSGIHSGA,HWQQQSYLV,WQ LIHC B1 [p.D32V]VSGIHSGATTTAPSLSGKGNP QQSYLVS,QQQSYLVSG,QSYLVSGIH,YLVSGIHSGA,QQQS EEEDV YLVSGI,SHWQQQSYLV,WQQQSYLVSG,QQSYLVSGIH CTNN c.97T>C p.S33P MELDMAMEPDRKAAVSHWQQQSYL YLDPGIHSG,WQQQSYLDP,QQQSYLDPG,QQSYLDPGI,YL LIHC B1 D[p.S33P]PGIHSGATTTAPSLSGKGNP DPGIHSGA,WQQQSYLDPG,QQQSYLDPGI,QQSYLDPGIH EEEDVD CTNN c.98C>A p.S33Y MELDMAMEPDRKAAVSHWQQQSYL YLDYGIHSG,WQQQSYLDY,QQSYLDYGI,YLDYGIHSGA,H UCEC B1 D[p.S33Y]YGIHSGATTTAPSLSGKGNPE WQQQSYLDY,QQQSYLDYGI,QQSYLDYGIH EEDVD CTNN c.98C>G p.S33C MELDMAMEPDRKAAVSHWQQQSYL YLDCGIHSG,WQQQSYLDC,QQSYLDCGI,YLDCGIHSGA,Q LIHC,UCEC B1 D[p.S33C]CGIHSGATTTAPSLSGKGNP QQSYLDCGI,QQSYLDCGIH EEEDVD CTNN c.98C>T p.S33F MELDMAMEPDRKAAVSHWQQQSYL YLDFGIHSG,WQQQSYLDF,QQSYLDFGI,QSYLDFGIH,YLDF UCEC B1 D[p.S33F]FGIHSGATTTAPSLSGKGNPE GIHSGA,HWQQQSYLDF,QQQSYLDFGI,QQSYLDFGIH EEDVD CTNN c.1341de|A p.I447 VHLGACGALKNISFGRDQDNKIAIK[p.I KIAIKTVMV,KLLPEPCGI,AIKTVMVCL,LVIWTLLKL,RLVI STAD D1 fs 447fs]TVMVCLPLCDCFERLVIWTLLKLL WTLLK,KTVMVCLPL,IFHPMTQSK,QSKWRLWTM,KWRLWT PEPCGIFHPMTQSKWRLWTMHCMP* MHC,EPCGIFHPM,NKIAIKTVM,FERLVIWTL,LLPEPCGIF,S KWRLWTMH,WRLWTMHCM,LPEPCGIFH,RLVIWTLLKL,L VIWTLLKLL,GIFHPMTQSK,CFERLVIWTL,KLLPEPCGIF, IFHPMTQSKW,KWRLWTMHCM,HPMTQSKWRL,TQSKWRL WTM,IAIKTVMVCL,IKTVMVCLPL,FERLVIWTLL,LPLCDCF ERL,PEPCGIFHPM CISC c.315de|T p.F105 NSGHFTIIYNQGFEIVLNDYKWFAF[p.F FLSIKKRAA,KWFAFLSIK,WFAFLSIKK,LSIKKRAAR,FAFL STAD fs 105fs]LSIKKRAAR* SIKKR,YKWFAFLSI,NDYKWFAFL,KWFAFLSIKK,DYKWF AFLSI,WFAFLSIKKR,FLSIKKRAAR CTSD c.267_268i p.P89 GPIPEVLKNYMDAQYYGEIGIGTPP[p.P GLLQPVGPL,HLREEWYLV,HSRLRHGLL,RLRHGLLQP,QQR STAD nsC fs 89fs]PVLHSRLRHGLLQPVGPLHPLQTA QVQHLR,VQHLREEWY,QPVGPLHPL,IGIGTPPPV,LRHGLL GHRLLDPPQVQQRQVQHLREEWYLV* QPV,LQTAGHRLL,VQQRQVQEIL,RQVQHLREE,RLRHGLLQ PV,VLHSRLRHGL,HSRLRHGLLQ,QVQHLREEWY,EIGIGTP PPV,PPPVLHSRL,HPLQTAGHRL,IGIGTPPPVL,LQPVGPL HPL,RQVQHLREEW,VQHLREEWYL,GEIGIGTPPP CTTN c.1259C>T p.S420 TSSTPPLPSNAAPPTAQTPGIAPQN[p.S LQAPPMHSL,PQNLQAPPM,NLQAPPMHSL,QTPGIAPQN UCEC BP2 L 420L]LQAPPMHSLHSPCANTSLHPGLN L,APQNLQAPPM,LQAPPMHSLH PRI CTTN c.490C>T p.R164 LEMEKLQLQALEQEHKKLAARLEEE[p.R CGKNKQVVL,KLAARLEEEC,AARLEEECGK CRC BP2 C 164C]CGKNKQVVLMLVKECKQLSGKVI EEA CUBN c.1786G>T p.G596 EHLRNGRGFTVRWETQQPECGGILT[p. ILTCPYGSI,LTCPYGSIK,CGGILTCPY,ILTCPYGSIK LUAD C G596C]CPYGSIKSPGYPGNYPPGRDCV WIVV CUBN c.8448C>G p.I281 GGGFYATWNTQTLGCGGIFHSDNGT[p. TMRSPHWPQ,IFHSDNGTM,TMRSPHWPQN,IFHSDNGT KIRP 6M I2816M]MRSPHWPQNFPENSRCSWT MR,GIFHSDNGTM,MRSPHWPQNF AITHKSK CUL1 c.1453G>A p.E485 DVFQKFYAKMLAKRLVHQNSASDDA[p. KASMISKLK,DAKASMISK,AKASMISKL,SASDDAKASM BLCA K E485K]KASMISKLKQACGFEYTSKLQR MFQD CUL7 c.1113G>C p.L371 QAQPSFRRSRRFRPRSEFASGNTYA[p.L ASGNTYAFY,FASGNTYAF,YAFYVRDTL,FASGNTYAFY,EFA LUAD F 371F]FYVRDTLQPGMRVRMLDDYEEIS SGNTYAF,TYAFYVRDTL,SGNTYAFYVR AGD CUL9 c.5178T>G p.D172 SPRCWPVSPLCYLYHPRKCLPTEFC[p.D CLPTEFCEA,LPTEFCEAL,EALDRFSSF,CEALDRFSS,CLPTEF KIRC 6E 1726E]EALDRFSSFYSQSQNHPVLDMG CEAL,EALDRFSSFY,TEFCEALDRF,CEALDRFSSF PHRR CUX1 c.1316_131 p.A439 LSGSARRKGKDQPESRRPGSLPAPP[p.A LPAPPSFSV,APQPGGAGF,GSLPAPPSF,QPGGAGFQY,SLP STAD 7insC fs 439fs]SFSVAPQPGGAGFQY* APPSFSV,FSVAPQPGGA,LPAPPSFSVA CWC2 c.1090A>G p.K364 EELERKRQEMMENAKWREEERLNIL[p. RLNILERHAK KIRC 5 E K364E]ERHAKDEEREQRLEKLDSRDGK FIHR CXCL9 c.366G>C p.K122 KKQKNGKKHQKKKVLKVRKSQRSRQ[p. KSQRSRQNK LUAD N K122N]NKTT* CXCR4 c.1033G>C p.E345 VSRGSSLKILSKGKRGGHSSVSTES[p.E3 STESQSSSF,SQSSSFHSS,VSTESQSSSF LUAD Q 45Q]QSSSFHSS* CXXC1 c.468G>C p.Q156 MLARGSASPHKSSPQPLVATPSQHH[p. HHHQQQQQI TGCT H Q156H]HQQQQQIKRSARMCGECEAC RRTEDC CXorf c.127G>A p.V43I QTPSTSSTKGRKKGKTPRQRRSRSG[p. RQRRSRSGI,QRRSRSGIK,RSRSGIKGL,RSRSGIKGLK,RQRR KIRC 51B V43I]IKGLKTTRKAKRPLRGSSSQKAGE SRSGIK,GIKGLKTTRK,RRSRSGIKGL TN CXorf c.593G>T p.R198 LLHLSGKMPPGINSSQSLPVDNHEK[p. LPVDNHEKM,HEKMVIQLH,HEKMVIQLHL,LPVDNHEKM LUAD 59 M R198M]MVIQLHLQHSSLLDFLNAQGG V CISHV CYP11 c.1492C>G p.R498 LVRVFLYSLGRNPALFPRPERYNPQ[p.R RYNPQGWLDI LUAD B1 G 498G]GWLDIRGSGRNFYHVPFGFGMR QCLG CYP19 c.1216T>C p.F406 DVIDGYPVKKGTNIILNIGRMHRLE[p.F IGRMHRLEL,MHRLELFPK,ELFPKPNEF,GRMHRLELF,RMH TGCT A1 L 406L]LFPKPNEFTLENFAKNVPYRYFQP RLELFPK,LFPKPNEFTL,NIGRMHRLEL,IGRMHRLELF,LELFP FG KPNEF CYP19 c.338G>T p.S113 WISGEETLIISKSSSMFHIMKHNHY[p.S HIMKHNHYI,YISRFGSKL,HYISRFGSK,ISRFGSKLG,KHNHYI THCA A1 I 113I]ISRFGSKLGLQCIGMHEKGIIFNN SRF,HYISRFGSKL,IMKHNHYISR,NHYISRFGSK,ISRFGSKLG NP L,MKHNHYISRF,FHIMKHNHYI CYP1A c.1447G>A p.V483 CIGEVLAKWEIFLFLAILLQQLEFS[p.V48 LLQQLEFSM,FSMPPGVKV,MPPGVKVDL,QQLEFSMPP,LE BRCA 2 M 3M]MPPGVKVDLTPIYGLTMKHARCEH FSMPPGV,ILLQQLEFSM,QLEFSMPPGV,SMPPGVKVDL,L VQ QQLEFSMPP,QQLEFSMPPG CYP27 c.335C>A p.P112 LYKAKYGPMWMSYLGPQMHVNLASA ASAQLLEQV,HVNLASAQL,VNLASAQLL,SAQLLEQVM,LAS LUAD A1 Q [p.P112Q]QLLEQVMRQEGKYPVRND AQLLEQV,HVNLASAQLL,MHVNLASAQL,ASAQLLEQVM MELWKEHR CYP2B c.1331C>A p.A444 ALKKTEAFIPFSLGKRICLGEGIAR[p.A44 IAREELFLF,AREELFLFF,EELFLFFTT,GEGIAREEL, LUAD 6 E 4E]EELFLFFTTILQNFSMASPVAPEDID REELFLFFT,GIAREELFLF,IAREELFLFF,EELFLFFTTI, GEGIAREELF,REELFLFFTT CYP2D c.1055A>G p.H352 VQRRVQQEIDDVIGQVRRPEMGDQA[p. MGDQARMPY,RMPYTTAVI,QARMPYTTA,ARMPYTTAV, GBM 6 R H352R]RMPYTTAVIHEVQRFGDIVPL QARMPYTTAV,EMGDQARMPY,RPEMGDQARM,ARMPY GVTHM TTAVI,RMPYTTAVIH CYP4A c.553G>T p.V185 GLMADSVRVMLDKWEELLGQDSPLE[p. LGQDSPLEF,GQDSPLEFF,LEFFQHVSL,EFFQHVSLM,SPLE OV 11 F V185F]FFQHVSLMTLDTIMKCAFSH FFQFIV,FFQHVSLMTL,DSPLEFFQFIV,LLGQDSPLEF,LEFFQ QGSIQV HVSLM,LGQDSPLEFF CYP4B c.1302G>T p.E434 HIYALHRNSAVWPDPEVFDSLRFST[p.E SLRFSTDNQA,RFSTDNASK,TDNASKRHPF CRC 1 D 434D]DNASKRHPFAFMPFSAGPRNCI GQQF CYP7B c.995A>C p.K332 YLLRHPEAMAAVRDEIDRLLQSTGQ[p. QTKGSGFPI,RLLQSTGQTK,GQTKGSGFPI,TKGSGFPIHL STAD 1 T K332T]TKGSGFPIHLTREQLDSLICLESSI F DAB2I c.481G>A p.E161 ILGQDYCFEVTTSSGSKCFSCRSAA[p.E1 CFSCRSAAK,FSCRSAAKR,RSAAKRDKW,KCFSCRSAAK,SC BRCA P K 61K]KRDKWMENLRRAVHPNKDNSRR RSAAKRDK,CFSCRSAAKR,AKRDKWMENL VEHI DACH c.1615C>T p.R539 TMQKRLKKEKKTKRKLQEALEFESK[p.R FESKCREQV,EALEFESKCR CRC 2 C 539C]CREQVEQALKQATTSDSGLRML KDTG DACH c.1616G>T p.R539 TMQKRLKKEKKTKRKLQEALEFESK[p.R KLREQVEQA,EALEFESKL,FESKLREQV,KLREQVEQAL,EALE LUAD 2 L 539L]LREQVEQALKQATTSDSGLRMLK FESKLR,QEALEFESKL DTG DBC1 c.646G>A p.V216 AIKVTETRTGPLGCNSYDNLDSVSS[p.V NLDSVSSIL,ILLQSTESK,NLDSVSSILL,ILLQSTESKL, CRC I 216I]ILLQSTESKLHLQGLQIIFPQYL SILLQSTESK,YDNLDSVSSI QEK DBF4B c.761C>A p.S254 PFLKIEDESRKFRPFHHQFKSFPEI[p. KSFPEIYFL,SFPEIYFLG,QFKSFPEIY,FKSFPEIYF, CRC Y S254Y]YFLGPKDASPFEAPTTLGSMHH QFKSFPEIYF,HQFKSFPEIY,FKSFPEIYFL TRES DCAF c.737G>A p.R246 RMDPDMFNGSIAWHSEVGLPVYAHI[p. PVYAHIHPR,HIHPRDVEA,HIHPRDVEAI,VYAHIHPRDV,LP GBM 12L2 H R246H]HPRDVEAIPRASTNPSNRKVR VYAHIHPR ALAFS DCC c.1337G>A p.R446 AIPSSSVLPSAPRDVVPVLVSSRFV[p.R4 LVSSRFVHL,SSRFVHLSW,VLVSSRFVH,VHLSWRPPA, LUAD H 46H]HLSWRPPAEAKGNIQTFTVFFSRE VLVSSRFVHL,FVHLSWRPPA,HLSWRPPAEA,SSRFVHL GD SWR,VSSRFVHLSW DCHS c.703de|C p.R235 LDRENRSHYMLQLEAYDGGSPPRRA[p. SPPRRARPC STAD 1 fs R235fs]RPCWT* DCHS c.6447C>A p.F214 TRENTYVEYSIISGNSQNNFHVETK[p.F KLFHSEYPY,LFHSEYPY,NFHVETKLF,ETKLFHSEY,KLFHSE CRC 2 9L 2149L]LFHSEYPYKQVGYLVLLHSLDRE YPYK,NNFHVETKLF,VETKLFHSEY,TKLFHSEYPY ASA DCLK2 c.1646C>A p.S549 HGLSIVHRDIKPENLLVCEYPDGTK[p.S5 YLKLGDFGL,CEYPDGTKY,TKYLKLGDF,YLKLGDFGLA,KYLK CRC Y 49Y]YLKLGDFGLATWEGPLYTVCGTPT LGDFGL,YPDGTKYLKL,CEYPDGTKYL Y DCLRE c.82T>A p.F28I GVLIPHTPIAVDFWSLRRAGTARLF[p.F RLFILSHMH,RAGTARLFI,ARLFILSHM,ILSHMHSDHT,GTA TGCT 1B 28I]ILSHMHSDHTVGLSSTWARPLYCSP RLFILSH,RAGTARLFIL,TARLFILSHM,RRAGTARLFI I DCT c.1595G>A p.R532 LVVMGTLVALVGLFVLLAFLQYRRL[p.R RLQKGYTPL,FLQYRRLQK,LQKGYTPLM,QYRRLQKGY,LQY UCEC Q 532Q]QKGYTPLMETHLSSKRYTEEA* RRLQKG,RLQKGYTPLM,AFLQYRRLQK,LQYRRLQKGY,RRL QKGYTPL DCUN c.824T>C p.L275 EKDQRSLDINTAKCMLGLLLGKIWP[p.L LLLGKIWPP,LLGKIWPPF,KIWPPFPVF,PFPVFHQFL,GKIW THCA 1D4 P 275P]PFPVFHQFLEQSKYKVINKDQWC PPFPV,PPFPVFHQF,LLLGKIWPPF,LGKIWPPFPV,KIWPPF NVL PVFH,GKIWPPFPVF,WPPFPVFHQF DDC c.1297de|A p.I433 LVCFRLKGSNKVNEALLQRINSAKK[p.I4 SLSCALPSV,VLARWNLPM,ILPSWNSAV,CGFPCLSPK,CAL STAD fs 33fs]STWFHVTSGTSLSCALPSVLARW PSVLAR,CSGPGNTSK,ASCRNQKLK,ALPSVLARW,SWNSA NLPMCSGPGNTSKSWRPTCCEQRGSR VCGF,SAKKSTWFH,GSRSEASCR,INSAKKSTW,AKKSTWFH SEASCRNQKLKRDISENWNKKQINIILPS V,KKSTWFFIVT,FHVTSGTSL,SGTSLSCAL,LSCALPSVL,LKR WNSAVCGFPCLSPKLSRGL* DISENW,KQINIILPS,SAVCGFPCL,LPSWNSAVC,SLSCALPS VL,VLARWNLPMC,IILPSWNSAV,ILPSWNSAVC,CLSPKLSR GL,RSEASCRNQK,CALPSVLARW,KQINIILPSW,SAKKSTWF HV,SVLARWNLPM,SWRPTCCEQR,STWFHVTSGT,TSLSCA LPSV,NIILPSWNSA,NSAVCGFPCL,LPSVLARWNL,WNKKQ INIIL,RINSAKKSTW,INSAKKSTWF,WFHVTSGTSL,SEASCR NQKL,KLKRDISENW,CGFPCLSPKL,CEQRGSRSEA DDI1 c.824G>A p.R275 VNGHPLKAFVDSGAQMTIMSQACAE[p. AEQCNIMRL,SQACAEQCNI,AEQCNIMRLV CRC Q R275Q]QCNIMRLVDRRWAGVAKG VGTQRIIG DDX1 c.1126G>A p.A376 PYYGSRLAIPAAQLVVLPYQMLLHA[p.A LLHATTRQA,TTRQAAGIR,QMLLHATTR,YQMLLHATT,LH TGCT 1 T 376T]TTRQAAGIRLQDQVVIIDEAHNLI ATTRQAA,MLLHATTRQA,LLHATTRQAA,TTRQAAGIRL,Y DT QMLLHATTR,LPYQMLLHAT DDX1 c.622de|A p.K208 AERLEQLESGEEELVLAEYESDEEK[p.K2 MRMRMTWRK,RWRAEWMRM,EWMRMRMTW,RAEW TGCT 1 fs 08fs]RWRAEWMRMRMTWRKNT* MRMRM,WMRMRMTWR,RMRMTWRKN,EEKRWRAEW, AEWMRMRMT,WMRMRMTWRK,RWRAEWMRMR,RM RMTWRKNT,EWMRMRMTWR,KRWRAEWMRM,WRAE WMRMRM,AEWMRMRMTW,DEEKRWRAEW DDX1 c.382T>C p.*128 CLFLSLEPPPPRDHISHCLLSAQFH[p.*1 LLSAQFHQK,CLLSAQFHQK UCS 1L2 Q 28Q]QK* DDX1 c.488de|G p.G163 HPEVARLTPYEVDELRRKKEITVRG[p.G VLNPCLPSI,SIMLTSHNM,ITVRGEMFV,KEITVRGEM,GEM STAD 7 fs 163fs]EMFVLNPCLPSIMLTSHNM* FVLNPC,EMFVLNPCL,NPCLPSIML,LPSIMLTSH,FVLNPCLP SI,VLNPCLPSIM,EITVRGEMFV,KKEITVRGEM,KEITVRGE MF,GEMFVLNPCL DDX3 c.447_448i p.F149 LAFQISKEYERFSKYMPNVKVAVFF[p.F VAVFFWWSV,AVFFWWSVY,FWWSVYQEG,VKVAVFFW KIRC 9B nsT fs 149fs]WWSVYQEG* W,KVAVFFWWSV,VAVFFWWSVY DDX5 c.986G>T p.R329 FNQGFYDCVIATDAEVLGAPVKGKR[p. LGRGPKGDK,KGKRLGRGPK,RLGRGPKGDK LUAD 6 L R329L]LGRGPKGDKASDPEAGVARGID FHHV DEFA1 c.270G>T p.W90 DCYCRIPACIAGERRYGTCIYQGRL[p.W IYQGRLCAF,IYQGRLCAFC,CIYQGRLCAF LUAD C 90C]CAFCC* DENN c.1496G>T p.R499 GRKKRKIPKLVLRINAIYEVRRGKK[p.R4 RGKKLVKRL,LVKRLSQSM,YEVRRGKKL,KLVKRLSQSM,EV LUAD D2A L 99L]LVKRLSQSMESNSGKVTDENSESD RRGKKLVK,YEVRRGKKLV SD DENN c.2063G>A p.R688 EVYCIVSRLGCFSLFSRILDEVEKR[p. KRQGISPAL,RQGISPALV,EKRQGISPAL,VEKRQGISPA LUAD D2A Q R688Q]QGISPALVQPLMRSVMEAPF PALGKT DENN c.1070C>A p.P357 LYRYSISGPHVLPIEKHISHFMHKV[p. FMHKVHFPS,KVHFPSPQR,HFPSPQRPR,ISHFMHKVF,SH CRC D4A H P357H]HFPSPQRPRILVQLSPHDNLI FMHKVHF,KVHFPSPQRP,ISHFMHKVHF,FMHKVHFPSP LSQPV DENN c.3242G>A p.R108 ESEKSSPAVSRSKTFTGRFKQQTPS[p.R RFKQQTPSQ,KQQTPSQTH,RFKQQTPSQT,KQQTPSQTHK, CRC D4C IQ 1081Q]QTHKERSTSLSALVRSSPHGSLG FKQQTPSQTH SVV DENN c.3068G>A p.G102 GELGDTGVMQIPKNLLEMTFECQNL[p. FECQNLEKL,LEKLTTVQI,CQNLEKLTTV,MTFECQNLEK HNSC D5B 3E G1023E]EKLTTVQIGHDNSGLLAKWLV DCVMV DGCR c.1552G>A p.E518 SVQDAPTKKEFVINPNGKSEVCILH[p.E ILHKYMQRV,KSEVCILHK,CILHKYMQR,KYMQRVLKV,HKY THCA 8 K 518K]KYMQRVLKVRPVYNFFECENPSE MQRVLK,SEVCILHKY,LHKYMQRVL,KSEVCILHKY,CILHKY PFG MQRV,ILHKYMQRVL,LHKYMQRVLK,KYMQRVLKVR,SEV CILHKYM,HKYMQRVLKV DGKB c.38C>T p.S13L MTNQEKWAHLSP[p.S13L]LEFSQLQK EKWAHLSPL,WAHLSPLEF,LEFSQLQKY,HLSPLEFSQL,KW BRCA YAEYSTKKLKDVLEEFHG AHLSPLEF,QEKWAHLSPL,LEFSQLQKYA DHPS c.147C>A p.F49L LPPESTQVRGYDFNRGVNYRALLEA[p.F ALLEALGTT,ALGTTGFQA,NYRALLEAL,LEALGTTGF,EALGT CESC 49L]LGTTGFQATNFGRAVQQVNAMIE TGFQA,LLEALGTTGF,VNYRALLEAL KKL DHRS c.653T>C p.I218 LGLNKTLAIELAPRNIRVNCLAPGL[p.I2 CLAPGLTKT,LTKTSFSRM,GLTKTSFSR,APGLTKTSF,TKTSFS LIHC 4 T 18T]TKTSFSRMLWMDKEKEESMKETL RML,GLTKTSFSRM,LTKTSFSRML,LAPGLTKTSF,TKTSFSR RIR MLW DHTK c.1229G>A p.R410 DIGKLVGCAIIHVNGDSPEEVVRAT[p.R TQLAFEYQR,VVRATQLAF,RATQLAFEY,EVVRATQLA,EEV CRC D1 Q 410Q]QL4FEYQRQFRKDVIIDLLCYRQ VRATQL,ATQLAFEYQR,VVRATQLAFE,VRATQLAFEY,QLA WGH FEYQRQF,EVVRATQLAF,EEVVRATQLA DHX9 c.119T>G p.V40G RKMTPSYEIRAVGNKNRQKFMCEVQ[p. GEGYNYTGM,FMCEVQGEGY,CEVQGEGYNY LUSC V40G]GEGYNYTGMGNSTNKKDAQS NAARDF DIAPH c.361G>A p.E121 ERSLNLSEKEVLDLFEKMMEDMNLN[p. MMEDMNLNK,LNKEKKAPL,KMMEDMNLNK,KEKKAPLR UCEC 2 K E121K]KEKKAPLRNKDFTTKREMVVQY NK,NLNKEKKAPL ISAT DICER c.5113G>A p.E170 KAYLLQAFTHASYHYNTITDCYQRL[p.E RLKFLGDAI,ITDCYQRLK,LKFLGDAIL,ITDCYQRLKF,RLKFLG CLL 1 5K 1705K]KFLGDAILDYLITKHLYEDPRQH DAIL,TITDCYQRLK,KFLGDAILDY,YQRLKFLGDA SPG DIRAS c.235G>T p.G79C VCTLQITDTTGSHQFPAMQRLSISK[p.G SISKCHAFI,RLSISKCHA,ISKCHAFIL,LSISKCHAF,MQRLSIS KIRC 1 79C]CHAFILVFSVTSKQSLEELGPIYKLI KC,KCHAFILVF,SISKCHAFIL,ISKCHAFILV,LSISKCHAFI, RLSISKCHAF,MQRLSISKCH,SKCHAFILVF DIS3 c.2339G>A p.R780 CSGMDNDFHHYGLASPIYTHFTSPI[p.R YTHFTSPIK,HFTSPIKRY,FTSPIKRYA,SPIKRYADV,IK MM K 780K]KRYADVIVHRLLAVAIGADCTYPE RYADVIV,KRYADVIVH,YTHFTSPIKR,IYTHFTSPIK,SPIKRYA LT DVI,THFTSPIKRY,IKRYADVIVH DISP1 c.2194_219 p.G732 EKVLPCIVIKFRYLWLFWFLALTVG[p.G FLALTVGLA,ALTVGLAYI,LTVGLAYIV,WFLALTVGL,LALTV SKCM 5GG>TT L 732L]LAYIVCINPKMKLPSLELSEFQVFR GLAY,FLALTVGLAY,ALTVGLAYIV,LAYIVCINPK,FWFLALTV SS GL,LALTVGLAYI DISP1 c.2287C>T p.R763 INPKMKLPSLELSEFQVFRSSHPFE[p.R7 RSSHPFECY,HPFECYDAE,CYDAEYKKLF,HPFECYDAEY,FRS CRC C 63C]CYDAEYKKLFMFERVHHGEELHM SHPFECY PIT DISP2 c.3062T>C p.F102 VAGTVLLTVGLLVLLEWQLNTAEAL[p.F NTAEALSLS,EALSLSASV,LNTAEALSL,AEALSLSAS,LSLSAS KIRC 1S 1021S]SLSASVGLSVDFTVNYCISYHLCP VGL,ALSLSASVGL,SLSASVGLSV,QLNTAEALSL,NTAEALSL HP SA,WQLNTAEALS,AEALSLSASV DKK2 c.689G>A p.R230 KPVLHQGEVCTKQRKKGSHGLEIFQ[p. EIFQHCDCA,FQHCDCAKGL,LEIFQHCDCA CRC H R230H]HCDCAKGLSCKVWKDATYSSK ARLHV DLC1 c.1049C>T p.A350 LATQEPTDNQVRLRKRKEIREDRDR[p. RVRLDSMVL,RDRVRLDSM,VRLDSMVLL,REDRDRVRL,RV CRC V A350V]VRLDSMVLLIMKLDQLDQDIEN RLDSMVLL,EIREDRDRVR,KEIREDRDRV ALST DLC1 c.2222G>C p.S741 ISALNGNRINVPMVRKRSVSNSTQT[p. RSVSNSTQTT BLCA,PRAD, T S741T]TSSSSQSETSSAVSTPSPVTRTRS TGCT,THCA LS DLC1 c.666G>T p.E222 ISLSEIKDAPKVNAVDTLNVKDIAP[p.E2 NVKDIAPDK CRC D 22D]DKQLLNSAVIAQQRRKPDPPKDE NER DLEU7 c.248C>T p.A83V RARPGPGREERGGGVGTRSRRTAAR[p. RSRRTAARV,RTAARVNSP,RSRRTAARVN,RTAARVNSPE ACC A83V]VNSPEEEVVRGAEGGAELLPFPR DRG DLG2 c.1871C>T p.S624 KRRVERKERARLKTVKFNAKPGVID[p.S GVIDLKGSF,NAKPGVIDLK,DLKGSFNDKR UCEC L 624L]LKGSFNDKRKKSFIFSRKFPFYKNK E DLGA c.1130de|G p.G377 GLLGPETKAKARTYHYLQVPQDDWG[p. WTRPGSTAV,TAAPRHLPK,ATSKPWGMR,VARMGRSPA, STAD P3 fs G377fs]VTPPVARMGRSPAAGCGAAA TSKPWGMRR,PVAPPAWTR,QVPQDDWGV,QSPDASPPV,S TSKPWGMRRAETQTAAPRHLPKQSPD TPGAPSLA,SPAAGCGAA,KPWGMRRAE,VPSPLDSSA,AR ASPPVAPPAWTRPGSTAVSHPGSTPGA MGRSPAA,RMGRSPAAG,GAAATSKPW,MRRAETQTA,RR PSLATAVPSPLDSSAMS* AETQTAA,TQTAAPRHL,KQSPDASPP,GSTPGAPSL,LATAV PSPL,SPPVAPPAW,LQVPQDDWGV,KQSPDASPPV,SLATA VPSPL,QTAAPRHLPK,ATSKPWGMRR,VARMGRSPAA,TS KPWGMRRA,GMRRAETQTA,RAETQTAAPR,VSHPGSTPG A,DWGVTPPVAR,VTPPVARMGR,DASPPVAPPA,SPAAGC GAAA,KPWGMRRAET,VPSPLDSSAM,WGVTPPVARM,CG AAATSKPW,MRRAETQTAA DLL3 c.952G>C p.D318 PRSFECTCPRGFYGLRCEVSGVTCA[p.D VTCAHGPCF,CEVSGVTCAH,GVTCAHGPCF BLCA H 318H]HGPCFNGGLCVGGADPDSAYIC HCPP DMBT c.4562G>T p.R152 SRASTAGSESTLALRLVNGGDRCRG[p. GLVEVLYQGS,RCRGLVEVLY LUAD 1 1L R1521L]LVEVLYQGSWGTVCDDYWDT NDANVV DMD c.5316G>C p.K177 DHCRKLVEPQISELNHRFAAISHRI[p.K1 ISHRINTGK,RINTGKASI,NTGKASIPL,AISHRINTGK,NTGKA BRCA 2N 772N]NTGKASIPLKELEQFNSDIQKLLE SIPLK,HRINTGKASI PL DMD c.9584G>A p.R319 NVPLCVDMCLNWLLNVYDTGRTGRI[p. TGRTGRIHV,HVLSFKTGI,TGRIHVLSF,TGRIHVLSFK,RTGRI CRC 5H R3195H]HVLSFKTGIISLCKAHLEDKYR HVLSF,RIHVLSFKTG,IFIVLSFKTGI YLFK DMPK c.131G>A p.R44H AGVGPGLPGAGAPARPSPGRPPGAG[p. HLRTGPGQV,HLRTGPGQVR CESC R44H]HLRTGPGQVRGRLLAVGPKSRV FQSV DMRT c.133T>A p.S45T PGVPPQGRAGGFGKASGALVGAASG[p. ALVGAASGT,GTSAGGSSR ACC 1 S45T]TSAGGSSRGGGSGSGASDLGA GSKKS DMRT c.317C>G p.T106 RGGPQPRPPLAPQASPAGTGPRERC[p. GPRERCSPA,GPRERCSPAG KIRP 2 S T106S]SPAGGGAEPRKLSRTPKCARCR NHGV DMXL c.7236C>A p.D241 GGGVKLVVKPRRQSENISAPPVLSE[p.D EEIDKHRRRF MM 2 2E 2412E]EIDKHRRRFNMRMLVPGRPVK DATPP DNAH c.5558G>T p.C185 GAPAGPAGTGKTETTKDLAKALGLL[p. KALGLLFVV,LAKALGLLF,AKALGLLFV,LAKALGLLFV,FVVT THCA 10 3F C1853F]FVVTNCGEGMDYRAVGKIFSG NCGEGM,DLAKALGLLF,AKALGLLFVV LAQCG DNAH c.5663G>A p.R188 DYRAVGKIFSGLAQCGAWGCFDEFN[p. QIDASVLSV,EFNQIDASV,DEFNQIDAS,NQIDASVLSV,DEF UCEC 10 8Q R1888Q]QIDASVLSVISSAIQTIRNALI NQIDASV HQLT DNAH c.4099C>T p.R136 QDIGPPAVKMLISAEGEGLVLPKKI[p.R KKICVRSAV,CVRSAVEQW,CVRSAVEQWL,LVLPKKICVR,L UCEC 14 7C 1367C]CVRSAVEQWLVNVEKSMFDVL PKKICVRSA KKERY DNAH c.10099G> p.E336 LNLRIKYIIDHFTLSIYNNVCRSLF[p.E33 SLFQKDKLL,NVCRSLFQK,LFQKDKLLF,QKDKLLFSL,FQKDK CESC 3 C 7Q 67Q]QKDKLLFSLLLTIGIMKQKKEITEEV LLFSL,SLFQKDKLLF DNAH c.11465G>T p.R382 QKLEISAETEVQINSAREEYRPVAT[p.R3 VATLGSILY,TLGSILYFL,ATLGSILYF,RPVATLGSI,EEYRP LUAD 5 2L 822L]LGSILYFLITEMRLVNEMYQTSLR VATL,PVATLGSILY,ATLGSILYFL,TLGSILYFLI,RPVATLG QF SIL,REEYRPVATL,VATLGSILYF DNAH c.2225G>A p.R742 LFRETECMAQMGLEVSPLATSLFQK[p. LFQKQDRYK,SLFQKQDRY,KQDRYKRNF,SLFQKQDRYK,TS SKCM 5 Q R742Q]QDRYKRNFSNMKMMLAEYQR LFQKQDRY,LFQKQDRYKR,QKQDRYKRNF VKSKIP DNAH c.2945G>A p.R982 ELLSHFNHQNMDALLKVTRNTLEAI[p. NTLEAIHKR,AIHKRIHSSH,NTLEAIHKRI,HKRIHSSHTI CRC 5 H R982H]HKRIHSSHTINFRDSNSASNMK QNSL DNAH c.5389C>G p.Q179 TIELDKPVMAEGNVEVWLNSLLEES[p. ESESSLHLV,LLEESESSL,ESSLHLVIR,EESESSLHL,SESS HNSC 5 7E Q1797E]ESSLHLVIRQAAANIQETGFQL LHLVI,SLLEESESSL,LEESESSLHL,EESESSLHLV TEFL DNAH c.671G>A p.R224 FLSSLEGFVNVLSGAQESLKEKVNL[p.R LQKCDILEL,NLQKCDILEL,SLKEKVNLQK,LQKCDILELK CRC 5 Q 224Q]QKCDILELKTLKEPTDYLTLANNP ET DNAH c.9590G>A p.R319 HVTPKSYLSFIQGYKFIYGEKHVEV[p.R3 EKHVEVQTL,HVEVQTLANR,GEKHVEVQTL,VEVQTLANR OV 5 7Q 197Q]QTLANRMNTGLEKLKEASESVA M ALSK DNAH c.9706G>A p.D323 KEASESVAALSKELEAKEKELQVAN[p.D ANNKADMVLK,QVANNKADMV,LQVANNKADM,KELQV SKCM 5 6N 3236N]NKADMVLKEVTMKAQAAEKV ANNKA KAEVQK DNAH c.8882G>A p.R296 LCKGRDIPCSDDCSLMGTLGEAVTI[p.R IQTWNIAGL,GEAVTIQTW,TIQTWNIAGL,EAVTIQTWNI UCEC 7 1Q 2961Q]QTWNIAGLPSDSFSIDNGIIIMN ARR DNAH c.4639G>A p.D154 LESIFTGSEDIRAQLPQDSKRFEGI[p.D1 NIDFKELAY,RFEGINIDF,SKRFEGINI,RFEGINIDFK, CRC 9 7N 547N]NIDFKELAYDAQKIPNVVQTTNK INIDFKELAY,KRFEGINIDF PGL DNAH c.8979C>G p.S299 KFPAIVNCTAIHWFHEWPQQALESV[p. SVRLRFLQN,RLRFLQNTE,QALESVRLR,QQALESVRL, LUAD 9 3R S2993R]RLRFLQNTEGIEPTVKQSISKF ALESVRLRF,LESVRLRFL,SVRLRFLQNT,RLRFLQNTEG, MAFV QALESVRLRF DNAI2 c.691G>T p.V231 PNKPELALKPSSPLVTLEFNPKDSH[p.V2 NPKDSHLLL,SHLLLGGCY,LEFNPKDSHL LUAD L 31L]LLLGGCYNGQIACWDTRKGSLVAE LS DNAJ c.578de|A p.K193 AVVWSIYLEKQLDELLSRKKREKKK[p.K RVWMYQNSV,RLAARVWMY,MYQNSVLQK,VWMYQNS STAD C1 fs 193fs]RLAARVWMYQNSVLQKKMKD VL,REKKKRLAA,KKRLAARVW,KRLAARVWM,WMYQNSV C* LQ,WMYQNSVLQK,KKRLAARVWM,RVWMYQNSVL,MY QNSVLQKK,KRLAARVWMY,YQNSVLQKKM,KKKRLAARV W,ARVWMYQNSV DNAJ c.239T>A p.I80K FKKLALKLHPDKNPNNPNAHGDFLK[p.I NAHGDFLKK,KNRAYEVLK,LKKNRAYEV,KKNRAYEVL,FLKK MM C10 80K]KNRAYEVLKDEDLRKKYDKYGEKG NRAYEV,GDFLKKNRAY,LKKNRAYEVL LE DNAJ c.404G>A p.R135 DLMLEESDKTHTTKMENEECNEQRE[p. EQREKKKEEL,KKKEELASTA MM C12 K R135K]KKKEELASTAEKTEQKEPKPLEK SVS DNAJ c.3742G>A p.E124 TPRLQSNTRALYQYCPIPIINYPQL[p.E1 PIINYPQLK,KNELFCNIY,YPQLKNELF,LKNELFCNI,QLKN UCEC C13 8K 248K]KNELFCNIYYLKQLCDTLRFPDWP ELFCNI,NYPQLKNELF,KNELFCNIYY,INYPQLKNEL,LKNE IK LFCNIY DNAJ c.181G>A p.E61K LMYHPDKQSTDVPAGTVEECVQKFI[p. KFIKIDQAW,FIKIDQAWK,IKIDQAWKI,FIKIDQAWKI,KFIKI CRC C24 E61K]KIDQAWKILGNEETKREYDLQRC DQAWK,QKFIKIDQAW,IKIDQAWKIL EDD DNAS c.634G>A p.D212 CASLTKKRLDKLELRTEPGFHWVIA[p.D VIANGEDTTV CESC E1L1 N 212N]NGEDTTVRASTHCTYDRVVLHG ERCR DNM2 c.1134G>C p.E378 TLELSGGARINRIFHERFPFELVKM[p.E3 LVKMDFDEK,FPFELVKMDF LIHC D 78D]DFDEKDLRREISYAIKNIHGVRTGL F DNM2 c.2371_2 p.P791 QRRPVSSIHPPGRPPAVRGPTPGPP[p. LLLGAPNPI,CSRGGSSLL,SRGGSSLLL,NPIPAWTPE,IPAWT STAD 372insC fs P791fs]PDSCSRGGSSLLLGAPNPIPAW PERV,SLLLGAPNPI,LLGAPNPIPA,CSRGGSSLLL,NPIPAWT TPERVCQQ* PER,LGAPNPIPAW DNMB c.232A>C p.T78P SSFVEIVTIPSLKEGERLFVCICEF[p.T FPSQELDNL KIRC P 78P]PSQELDNLPLHRGDLVILDGIPTAGW DNMT c.1294G>A p.E432 LTCFSVYCKHGHLCPIDTGLIEKNI[p.E4 GLIEKNIKL,KLFFSGSAK,IEKNIKLFF,IKLFFSGSA,NIKLFFSGS CRC 1 K 32K]KLFFSGSAKPIYDDDPSLEGGVNGK A,GLIEKNIKLF N DNMT c.151G>A p.E51K RRLKDLERDSLTEKECVKEKLNLLH[p.E5 KLNLLHKFL,KEKLNLLHK,EKLNLLHKF,LLHKFLQTEI,KEKLN UCEC 1 1K]KFLQTEIKNQLCDLETKLRKEELSEE LLHKF DNMT c.2984G>A p.R995 PEHYRKYSDYIKGSNLDAPEPYRIG[p.R9 QIKEIFCPK,RIGQIKEIF,GQIKEIFCPK,QIKEIFCPKK,APE TGCT 1 Q 95Q]QIKEIFCPKKSNGRPNETDIKIRVN PYRIGQI,YRIGQIKEIF K DNMT c.4591G>C p.E153 RHNHWAGLYGRLEWDGFFSTTVTNP[p. VTNPQPMGK,TTVTNPQPM,QPMGKQGRV,TVTNPQPM CRC 1 1Q E1531Q]QPMGKQGRVLHPEQHRVV GK,QPMGKQGRVL,STTVTNPQPM SVRECARS DNMT c.2207G>A p.R736 NDLSIVNPARKGLYEGTGRLFFEFY[p.R HLLHDARPK,FYHLLHDAR,FEFYHLLHD,EFYHLLHDAR,FEF LAML 3A H 736H]HLLHDARPKEGDDRPFFWLFEN YHLLHDA VVAM DNMT c.2644C>T p.R882 DILWCTEMERVFGFPVHYTDVSNMS[p. VSNMSCLAR,NMSCLARQR,DVSNMSCLA,YTDVSNMSCL, LAML 3A C R882C]CLARQRLLGRSWSVPVIRHLFA NMSCLARQRL,CLARQRLLGR,DVSNMSCLAR,SNMSCLAR PLKE QR DNMT c.2645G>A p.R882 DILWCTEMERVFGFPVHYTDVSNMS[p. YTDVSNMSH,VSNMSHLAR,MSHLARQRL,NMSHLARQR, LAML 3A H R882H]HLARQRLLGRSWSVPVIRHLF DVSNMSHLA,YTDVSNMSHL,HLARQRLLGR,MSHLARQRL APLKE L,DVSNMSHLAR,SNMSHLARQR,NMSHLARQRL DNMT c.274C>T p.R92 TQDLTGDGDGEDGDGSDTPVMPKLF[p. VMPKLFWET,KLFWETRTR,MPKLFWETR,TPVMPKLFW,V CRC 3B W R92W]WETRTRSESPAVRTRNNNSV MPKLFWETR SSRERH DOCK c.2590G>A p.E864 SKMFTEFILNVPMGLLTIQKLYCLI[p.E8 KLYCLIKIV,IQKLYCLIK,IKIVHSDLF,CLIKIVHSDL,TIQKLY CRC 1 K 64K]KIVHSDLFTQHDCREILLPMMTDQ CLIK,LIKIVHSDLF,IQKLYCLIKI LK DOCK c.5489C>T p.A183 NENILVEQLYMCVEFLWKSERYELI[p.A LIVDVNKPI,ELIVDVNKPI,WKSERYELIV,SERYELIVDV CRC 10 0V 1830V]VDVNKPIIAVFEKQRDFKKLSDL YYD DOCK c.505C>G p.Q169 FEIDEDCEKDEDSSSLCSQKGGVIK[p.Q VIKEGWLHKA,GVIKEGWLHK,KEGWLHKANV TGCT 11 E 169E]EGWLHKANVNSTITVTMKVFKR RYFY DOCK c.3547C>T p.R118 ELFSLLTQLFGPYPSLLEKVEQETW[p.R1 TWCETGISF,QETWCETGI,VEQETWCET,CETGISFVT,ETW CRC 3 3C 183C]CETGISFVTSVTRLMERLLDYRDC CETGISF,CETGISFVTS MK DOCK c.529G>A p.E177 IDHGNRMLGLDLVVRDDNGNILDPD[p. KTSTIALFK,ILDPDKTSTI,KTSTIALFKA,DPDKTSTIAL CRC 5 K E177K]KTSTIALFKAHEVASKRIEEKIQE EK DOCK c.3332 p.L111 TLISMRLEFLRILCSHEHYLNLNLF[p.L11 HYLNLNLFL KICH 8 de|T 1fs 11fs]L* DOCK c.531_532 p.A177 HKTLPKQTFESETLECSEPAAQAGP[p.A AQAGPPPLK,RAVRRVWER,GPPPLKRAV,AAQAGPPPL,LK KIRC 8 insG fs 177fs]PPLKRAVRRVWERPRHCL* RAVRRVW,AAQAGPPPLK,AVRRVWERPR,RVWERPRHCL DOK5 c.820C>T p.R274 KMSERAASLSTMVPLPRSAYWQHIT[p. SAYWQHITW,YWQHITWQH,WQHSTGQLY,WQHITWQH CRC W R274W]WQHSTGQLYRLQDVSSPLKLH S,RSAYWQHITW,YWQHITWQHS,WQHSTGQLY,WQHIT RTETF WQHST,ITWQHSTGQL DOK7 c.1382G>A p.G461 GQTSAGCPSGWLGTRRRGLVMEAPQ[p. APQDSEATL,MEAPQDSEA,MEAPQDSEAT ACC D G461D]DSEATLPGPAPGEPWEAGG PHAGPPP DOPE c.3586G>A p.E119 KAGAKLSLVRVDSDKTQASESFSSD[p.E ASESFSSDK,KEADLELQA,QASESFSSDK,KEADLELQAL,SES BLCA Y2 6K 1196K]KEADLELQALTTSRLLKQQRER FSSDKEA QEAV DOPE c.6143A>C p.Y204 FEQKAMLLKRQAFAVFSGELDQYHL[p. SLPLIQERL,QYHLSLPLI,LSLPLIQER,DQYHLSLPL,GELDQYH KIRC Y2 8S Y2048S]SLPLIQERLTDNLRVGQTSIVA LS,HLSLPLIQER,GELDQYHLSL,LDQYHLSLPL,DQYHLSLPLI, AQMF LSLPLIQERL DPCR c.2302_23 p.L768 NRERTANENTTPSPAQPTENGDRTP[p. TENGDRTPA KIRC 1 04de|TTG de| L768de|]ANEKTTPSLAEPTENGKRTPF ANEKTTS DPEP1 c.31G>T p.V11L MWSGWWLWPL[p.V11L]LAVCTADFF WLWPLLAVC,GWWLWPLLA,WWLWPLLAV,LLAVCTADF, BRCA RDEAERIMRDSPVIDGH SGWWLWPLL,LAVCTADFF,WPLLAVCTA,WLWPLLAVCT, WSGWWLWPLL,GWWLWPLLAV,LAVCTADFFR,LLAVCTA DFF DPP10 c.547G>A p.V183 TASYVIYNIHTREVWELNPPEVEDS[p.V EVEDSILQY,ILQYAAWGV,VEDSILQYA,NPPEVEDSI,SILQY GBM I 183I]ILQYAAWGVQGQQLIYIFENNIYY AAWGV,EVEDSILQYA,PEVEDSILQY,VEDSILQYAA QP DPP6 c.2271G>T p.L757 TFTCGSALSPITDFKLYASAFSERY[p.L75 FSERYFGLH,AFSERYFGL,ASAFSERYF,ERYFGLHGL,SAFSE LUAD F 7F]FGLHGLDNRAYEMTKVAHRVSALE RYFGL,YASAFSERYF,SERYFGLHGL EQ DPP8 c.493G>A p.G165 QATLDYGMYSREEELLRERKRIGTV[p.G RKRIGTVRI,IGTVRIASY,TVRIASYDY,KRIGTVRIA,GTVRIAS CRC R 165R]RIASYDYHQGSGTFLFQAGSGIY YDY,RERKRIGTVR,RIGTVRIASY,TVRIASYDYH,RKRIGTVRI HVK A DPY19 c.1134C>A p.F378 ILKYLTSKIFGIADDAHIGNLLTSK[p.F37 LTSKLFSYK,LLTSKLFSY,GNLLTSKLF,SKLFSYKDF,KLFSYK CRC LI L 8L]LFSYKDFDTLLYTCAAEFDFMEKETP DFDT,LLTSKLFSYK,NLLTSKLFSY,IGNLLTSKLF DPY19 c.745G>T p.V249 MLLVTHILRATKLYRGSLIALCISN[p.V24 LIALCISNL,CISNLFFML,IALCISNLF,LFFMLPWQF,ALCISNL KIRP L1 L 9L]LFFMLPWQFAQFVLLTQIASLFAVY FF,LCISNLFFM,SNLFFMLPW,SLIALCISNL,ALCISNLFFM,IA V LCISNLFF,NLFFMLPWQF,LIALCISNLF,ISNLFFMLPW DPY19 c.628A>G p.M21 INAIKRFHLYPEVIIASWYCTFMGI[p.M2 CTFMGIVNL,CTFMGIVNLF,SWYCTFMGIV PRAD L2 0V 10V]VNLFGLETKTCWNVTRIEPLNEVQ SC DQX1 c.1514G>A p.R505 ASCEFDCVDEMLTLAAMLTAAPGFT[p. APGFTHPPL,MLTAAPGFTH GBM H R505H]HPPLSAEEAALRRALEHTDGDH SSLI DRD5 c.825C>A p.S275 RIAQVQIRRISSLERAAEHAQSCRS[p.S2 HAQSCRSRA,RSRAACAPD,AQSCRSRAA,RSRAACAPDT,R GBM R 75R]RAACAPDTSLRASIKKETKVLKTLS AACAPDTSL,AQSCRSRAAC V DSG4 c.383G>T p.R128 NPRTGEINITSVVDREITPLFLIYC[p.R12 FLIYCLALN,IYCLALNSR,TPLFLIYCL,FLIYCLALNS,ITPLFLIYC LUAD L 8L]LALNSRGEDLERPLELRVKVMDIND L,LIYCLALNSR,TPLFLIYCLA N DSP c.478C>G p.R160 CDAYQKRLLQLQEQMRALVKAISVP[p. AISVPGVRR,KAISVPGVR,GVRRASSKG,YKAISVPGV,KAISV HNSC G R160G]GVRRASSKGGGGYTCQSGSG PGVRR,LYKAISVPGV WDEFTK DST c.13228 p.A441 TICGKSVERQNKLEEALLFSGQFTD[p.A FTDSLQALI,SLQALIDWL,FSGQFTDSL,GQFTDSLQA,FTDSL LUAD G>T 0S 4410S]SLQALIDWLYRVEPQLAEDQPV QALID,SLQALIDWLY,GQFTDSLQAL,QFTDSLQALI HGDI DST c.5300C>A p.S176 ITLTRSLSVQDGLDEMLDWMGNVES[p. WMGNVESYL,MGNVESYLK,YLKEQGQVPL,WMGNVESYL UCEC 7Y S1767Y]YLKEQGQVPLNSTALQDIISKN K,DWMGNVESYL,ESYLKEQGQV,LDWMGNVESY IMLE DSTN c.301_302 p.F101 KDCRYALYDASFETKESRKEELMFF[p.F LMFFFVGTR,GTRTSTSEK,ELMFFFVGT,RKEELMFFF,EELM STAD insT fs 101fs]FVGTRTSTSEK* FFFVG,KEELMFFFV,LMFFFVGTRT,ELMFFFVGTR,SRKEEL MFFF,FFFVGTRTST,EELMFFFVGT,KEELMFFFVG DUOX c.2640C>A p.F880 SPEDKSRLMFTMYDLDENGFLSKDE[p. FLSKDELFT,GFLSKDELF,LFTMMRSFI,ELFTMMRSF,LSKDE CRC 2 L F880L]LFTMMRSFIEISNNCLSKAQLAE LFTM,SKDELFTMM,DELFTMMRS,FLSKDELFTM,ELFTM VVE MRSFI,NGFLSKDELF,LSKDELFTMM,DELFTMMRSF DVL2 c.1801 p.A601 YGGGSASSQHSEGSRSSGSTRSDGG[p. ALLHPEAQL,SLSPPAEGA,GAAFGGVGK,GPPSPSPAV,SPP CRC de|G fs A601fs]QGARGGPRSGPPSPSPAVAVS AEGAAF,EPTQGSIPM,IPMDRPLAW,RPLAWPSPT,VGKQV LSPPAEGAAFGGVGKQVGLAMGALLH GLAM,KQVGLAMGA,PEAQLGVPL,AQLGVPLIS,GSIPMDR PEAQLGVPLISEPTQGSIPMDRPLAWPS PL,LAWPSPTTP,AEGAAFGGV,AMGALLHPEA,LLHPEAQL PTTP* GV,AVAVSLSPPA,SLSPPAEGAA,KQVGLAMGAL,LISEPTQ GSI,STRSDGGQGA,RSGPPSPSPA,SPSPAVAVSL,HPEAQL GVPL,RPLAWPSPTT,LSPPAEGAAF,GVGKQVGLAM,SEPT QGSIPM,PEAQLGVPLI,AEGAAFGGVG DVL2 c.197T>G p.V66G GDFKSVLQRPAGAKYFFKSMDQDFG[p. SMDQDFGGV,KSMDQDFGGV,SMDQDFGGVK GBM V66G]GVKEEISDDNARLPCFNGRVVS WLVS DYNC c.2649G>T p.E883 KEWIVIGQVDMEALVEKHLFTVHDW[p. HLFTVHDWDK,TVHDWDKNFK,HDWDKNFKAL UCEC 2H1 D E883D]DKNFKALKIKGKEVERLPSAVK VDCL DYRK1 c.1633 p.Q545 DVPHKTHQAPASASSLPGTGAQLPP[p. HHQPHHHPR,LVVPHHQPH,SPDTLVVPH,LPPSPDTLV,QL STAD B de|C fs Q545fs]SPDTLWPHHQPHHHPRS* PPSPDTLV,AQLPPSPDTL,LPPSPDTLVV DYRK4 c.1402 p.K468 TASRRQTFFDSKGFPKNITNNRGKK[p.K TQIPRTSRW,DTQIPRTSR,RGKKDTQIPR STAD de|A fs 468fs]DTQIPRTSRWC* DZIP3 c.964A>C p.M32 NLKYPGENDQSFSGKKCLKEGCTGD[p. KEGCTGDLV,CLKEGCTGDL LUAD 2L M322L]LVRMLQCDVPGIVKILFEWRK DEYI E2F7 c.272T>G p.I91S PITPVKFVDRQQAEPWTPTANLKML[p. NLKMLSSAA,LKMLSSAAS,KMLSSAASP,MLSSAASPDI,LK TGCT I91S]SSAASPDIRDREKKKGLFRPIENKD MLSSAASP D EAF2 c.327de|A p.V109 CILIINHDTGECRLEKLSSNITVKK[p.V10 ITVKKQELK,IVKNNSNNK,KQELKEAVK,KKQELKEAV,QELK STAD fs 9fs]QELKEAVKFSIVKNNSNNKCGIQPG EAVKF,KEAVKFSIV,CGIQPGLPI,SIVKNNSNNK,ELKEAVKF LPIL* SI,KQELKEAVKF,CGIQPGLPIL EBAG c.559G>A p.E187 EEDAAWQAEEVLRQQKLADREKRAA[p. RAAKQQRKK,KQQRKKMEK,RAAKQQRKKM CRC 9 K E187K]KQQRKKMEKEAQRLMKKEQN KIGVKL EBF1 c.1058A>G p.D353 SYKSKQFCKGTPGRFIYTALNEPTI[p.D3 ALNEPTIGY,PTIGYGFQR,NEPTIGYGF,IGYGFQRLQK,GYG TGCT G 53G]GYGFQRLQKVIPRHPGDPERLPKE FQRLQKV,TALNEPTIGY,LNEPTIGYGF VI EBPL c.565C>G p.L189 YCWLYLFFFNGVWVLIPGLLLWQSW[p. GLLLWQSWV,LLWQSWVEL,WQSWVELKK,LLLWQSWVE KICH,KIRP, V L189V]VELKKMHQKETSSVKKFQ* L,LLWQSWVELK,WQSWVELKKM TGCT EBPL c.587A>C p.Q196 FFNGVWVLIPGLLLWQSWLELKKMH[p. KMHPKETSS,KMHPKETSSV KICH P Q196P]PKETSSVKKFQ* ECE2 c.760G>A p.D254 DRGVSPCEDFYQFSCGGWIRRNPLP[p. NGRSRWNTF,NPLPNGRSRW CESC N D254N]NGRSRWNTFNSLWDQNQAIL KHLLEN ECI2 c.164A>G p.K55R HMNRTAMRASQKDFENSMNQVKLLK[p. LLKRDPGNEV,SMNQVKLLKR TGCT K55R]RDPGNEVKLKLYALYKQATEGP CNMP ECM1 c.796G>A p.E266 EIGYSRCCHCRSHTNRLECAKLVWE[p.E KAMSRFCEA,VWEKAMSRF,LVWEKAMSR,AKLVWEKAM, BLCA K 266K]KAMSRFCEAEFSVKTRPHWCCT WEKAMSRFC,KLVWEKAMSR,LVWEKAMSRF,CAKLVWEK RQGE AM EDA c.174G>C p.L58F RAGEGNSCLLFLGFFGLSLALHLLT[p.L5 HLLTFCCYL,LTFCCYLEL,SLALHLLTF,TFCCYLELR,LHLLTFCC HNSC 8F]FCCYLELRSELRRERGAESRLGGSGT Y,LLTFCCYLEL,SLALHLLTFC,LTFCCYLELR,LSLALHLLTF,AL HLLTFCCY EDNR c.1349T>G p.L450 SRILKLTLYNQNDPNRCELLSFLLV[p.L4 LSFLLVWDY,LLVWDYIGI,SFLLVWDYI,WDYIGINMA,FLLV CRC B R 50R]WDYIGINMASLNSCINPIALYLVSK WDYIGI,LLSFLLVWDY,CELLSFLLVW,LVWDYIGINM R EEA1 c.1709 p.N570 EREDLYAKIQAGEGETAVLNQLQEK[p. QLQEKTIHY,QLQEKTIHYR,NQLQEKTIHY STAD de|A fs N570fs]TIHYRSK* EEF1A c.1294_12 p.T432 GKPMCVESFSDYPPLGRFAVRDMRQ[p. QLVAVGVIK,AVRDMRQLV,FAVRDMRQL,RDMRQLVAV,RQLV LIHC 1 95AC>TT L T432L]LVAVGVIKAVDKKAAGAGKVT AVGVI,QLVAVGVIKA,LVAVGVIKAV,AVRDMRQLVA, KSAQKA RQLVAVGVIK,FAVRDMRQLV EEF1A c.1253A>C p.Y418 SLKSGDAAIVEMVPGKPMCVESFSQ[p. ESFSQSPPL,SPPLGRFAV,SQSPPLGRF,SFSQSPPLGR,VESF BLCA,TGCT 2 S Y418S]SPPLGRFAVRDMRQTVAVGVIK SQSPPL,FSQSPPLGRF,SQSPPLGRFA NVEK EEF1B c.127A>G p.S43G YLADKSYIEGYVPSQADVAVFEAVS[p.S EAVSGPPPA,FEAVSGPPP,FEAVSGPPPA KIRP,PRAD, 2 43G]GPPPADLCHALRWYNHIKSYEKEK SKCM AS EEF2K c.2017G>A p.E673 TDCDEGGEYDGMQDEPRYMMLAREA MMLAREAKM,MLAREAKML,YMMLAREAK,AKMLFTGGY, BLCA K [p.E673K]KMLFTGGYGLEKDPQRSGDL LAREAKMLF,REAKMLFTG,YMMLAREAKM,MMLAREAK YTQAAE ML,KMLFTGGYGL,MLAREAKMLF,RYMMLAREAK,EAKML FTGGY,REAKMLFTGG EFCAB c.793G>C p.E265 MEQQIKSEKEQFLLKDTERFQARSQ[p. RFQARSQQL,RSQQLEQKL,SQQLEQKLL,QARSQQLEQK,E LUAD 4B Q E265Q]QLEQKLLCKEQELEQLTQKQKR RFQARSQQL,FQARSQQLEQ,RSQQLEQKLL LEGQ EFCAB c.1136G>A p.R379 NWKQFLTSFHEPQGLQVSSKGPLTK[p. SSKGPLTKK,GPLTKKNSI,VSSKGPLTKK,LTKKNSINSR BLCA,GBM, 6 K R379K]KNSINSRNESHKENIITKLFRHTE PRAD DH EFCAB c.3004G>A p.E100 DQSKTNYISICKMQEVLEECGCSLT[p.E SLTKGELTHL HNSC 6 2K 1002K]KGELTHLLNSWGVSRHDNAINY LDFL EGFR c.1786C>T p.P596 CTGRGPDNCIQCAHYIDGPHCVKTC[p. CVKTCSAGV,VKTCSAGVM,CVKTCSAGVM GBM S P596S]SAGVMGENNTLVWKYADAGH VCHLCH EGFR c.1787C>T p.P596 CTGRGPDNCIQCAHYIDGPHCVKTC[p. CVKTCLAGV,GPHCVKTCL,VKTCLAGVM GBM L P596L]LAGVMGENNTLVWKYADAGH VCHLCH EGFR c.1793G>C p.G598 GRGPDNCIQCAHYIDGPHCVKTCPA[p. CVKTCPAAV,VKTCPAAVM,AVMGENNTL,AVMGENNTLV, GBM A G598A]AVMGENNTLVWKYADAGHVC CVKTCPAAVM,AAVMGENNTL HLCHPN EGFR c.1793G>T p.G598 GRGPDNCIQCAHYIDGPHCVKTCPA[p. CVKTCPAVV,VKTCPAVVM,VVMGENNTLV,CVKTCPAVV GBM V G598V]VVMGENNTLVWKYADAGHVC M HLCHPN EGFR c.185T>G p.L62R KLTQLGTFEDHFLSLQRMFNNCEVV[p. MFNNCEVVR,EVVRGNLEI,VRGNLEITY,RMFNNCEVVR,V GBM L62R]RGNLEITYVQRNYDLSFLKTIQEV VRGNLEITY,CEVVRGNLEI AG EGFR c.2125G>A p.E709 QERELVEPLTPSGEAPNQALLRILK[p.E7 RILKKTEFK,ILKKTEFKK,QALLRILKK,LRILKKTEF,R GBM K 09K]KTEFKKIKVLGSGAFGTVYKGLWIP ILKKTEFKK,NQALLRILKK,LLRILKKTEF E EGFR c.2156G>C p.G719 PSGEAPNQALLRILKETEFKKIKVL[p.G7 ASGAFGTVY,VLASGAFGT,LASGAFGTV,KIKVLASGA,KVLA LUAD A 19A]ASGAFGTVYKGLWIPEGEKVKIPV SGAFG,IKVLASGAF,KKIKVLASG,VLASGAFGTV,ASGAFGT AI VYK,KIKVLASGAF,LASGAFGTVY,KKIKVLASGA,TEFKKIKVL A EGFR c.2235_224 p.ELRE GAFGTVYKGLWIPEGEKVKIPVAIK[p.E AIKTSPKANK,KVKIPVAIKT,KTSPKANKEI LUAD 9de|GGAAT A746de| LREA746de|]TSPKANKEILDEAYVMAS TAAGAGAA VDNPHVCRLLGICLTSTVQLIT GC EGFR c.2303G>T p.S768 AIKELREATSPKANKEILDEAYVMA[p.S MAIVDNPHV,VMAIVDNPH,DEAYVMAIV,LDEAYVMAI,IL LUAD I 768I]IVDNPHVCRLLGICLTSTVQLITQL DEAYVMAI,VMAIVDNPHV,AIVDNPHVCR,YVMAIVDNPH, M DEAYVMAIVD EGFR c.2512C>A p.L838 YLLNWCVQIAKGMNYLEDRRLVHRD[p. RLVHRDMAA,DMAARNVLV,MAARNVLVK,LVHRDMAAR, KIRC M L838M]MAARNVLVKTPQHVKITDFGL RDMAARNVL,RLVHRDMAAR,DMAARNVLVK,HRDMAA AKLLG RNVL,RDMAARNVLV EGFR c.2573T>G p.L858 LVHRDLAARNVLVKTPQHVKITDFG[p.L KITDFGRAK,HVKITDFGR,FGRAKLLGA,HVKITDFGRA,RAK LUAD R 858R]RAKLLGAEEKEYHAEGGKVPIKW LLGAEEK MAL EGFR c.2582T>A p.L861 RDLAARNVLVKTPQHVKITDFGLAK[p.L LAKQLGAEEK,KQLGAEEKEY LUSC Q 861Q]QLGAEEKEYHAEGGKVPIKWMA LESI EGFR c.323G>A p.R108 QEVAGYVLIALNTVERIPLENLQII[p.R10 QIIKGNMYY,LQIIKGNMY,LQIIKGNMYY,KGNMYYENSY GBM K 8K]KGNMYYENSYALAVLSNYDANKTG LK EGFR c.754C>T p.R252 SPSDCCHNQCAAGCTGPRESDCLVC[p. RESDCLVCC GBM C R252C]CKFRDEATCKDTCPPLMLYNPT TYQM EGFR c.865G>A p.A289 CPPLMLYNPTTYQMDVNPEGKYSFG[p. YSFGTTCVK,TTCVKKCPR,GKYSFGTTC,YSFGTTCVKK,KYSF GBM T A289T]TTCVKKCPRNYVVTDHGSCVR GTTCVK,GTTCVKKCPR,GKYSFGTTCV ACGAD EGFR c.866C>A p.A289 CPPLMLYNPTTYQMDVNPEGKYSFG[p. YSFGDTCVK,DTCVKKCPR,GKYSFGDTC,YSFGDTCVKK,KYS GBM D A289D]DTCVKKCPRNYVVTDHGSCVR FGDTCVK,GKYSFGDTCV ACGAD EGFR c.866C>T p.A289 CPPLMLYNPTTYQMDVNPEGKYSFG[p. YSFGVTCVK,KYSFGVTCV,VTCVKKCPR,GKYSFGVTC,YSFG GBM V A289V]VTCVKKCPRNYVVTDHGSCVR VTCVKK,KYSFGVTCVK,GVTCVKKCPR,GKYSFGVTCV ACGAD EGFR c.910C>T p.H304 VNPEGKYSFGATCVKKCPRNYVVTD[p. VVTDYGSCV,YVVTDYGSCV,WTDYGSCVR,CPRNYVVTDY GBM Y H304Y]YGSCVRACGADSYEMEEDGVR KCKKC EGR1 c.27G>C p.Q9H MAAAKAEM[p.Q9H]HLMSPLQISDPF AAKAEMHLM,AEMHLMSPL,MHLMSPLQI,MAAAKAEMH MM GSFPHSPTMDNYPK L,AAAKAEMHLM,KAEMHLMSPL,EMHLMSPLQI,AEMHL MSPLQ EGR1 c.994de|C p.P332 TSYQSQLIKPSRMRKYPNRPSKTPP[p.P LTLAQWSPV,TLAQWSPVI,AQWSPVIAA,KQTKVLWPL,VI STAD fs 332fs]TNALTLAQWSPVIAASPAPTSSP AASPAPT,AMNARGIPR,RLLPLTRPR,RLLPLIHPR,ATSASTQ ATSASTQARSPSSAASACATSAAATTSP AR,STCGRRTRK,CTVASPPRR,LWPLRPPPL,STQARSPSS,Q PTSAPTQAKSPSPATSVEESLPGAMNA ARSPSSAA,RSPSSAASA,ASACATSAA,KSPSPATSV,RSTCG RGIPRSTCGRRTRKQTKVLWPLRPPPLS RRTR,RTRKQTKVL,QTKVLWPLR,PTRPRLLPL,RPRLLPLTR, LPTRPRLLPLTRPRLLPLIHPRPPPHTHPL LTRPRLLPL,LIHPRPPPH,SLPGAMNAR,ESLPGAMNA,SPVI CPPPSPLPAPRPTHPLCTVASPPRRWPP AASPA,SPAPTSSPA,RPPPLSLPT,LPLTRPRLL,RPRLLPLIH,H RTPLFPLLSRPRSAASLPQLSPTPSAPPQ PRPPPHTH,RPPPHTHPL,SPLPAPRPT,APRPTHPLC,RPTHP GFRT* LCTV,SLPTRPRLL,SKTPPTNAL,TQARSPSSA,TQAKSPSPA, VEESLPGAM,LSLPTRPRL,CPPPSPLPA,ALTLAQWSPV,TLA QWSPVIA,VLWPLRPPPL,RLLPLTRPRL,GAMNARGIPR,RS TCGRRTRK,KTPPTNALTL,STQARSPSSA,ASACATSAAA,RG IPRSTCGR,CGRRTRKQTK,RTRKQTKVLW,KQTKVLWPLR,K VLWPLRPPP,LTRPRLLPLI,HTHPLCPPPS,ESLPGAMNAR,W SPVIAASPA,TTSPPTSAPT,RPSKTPPTNA,SPAPTSSPAT,AP TSSPATSA,SPATSASTQA,SPATSVEESL,LPGAMNARGI,W PLRPPPLSL,LPTRPRLLPL,HPLCPPPSPL,LPAPRPTHPL,APR PTHPLCT,RPTHPLCTVA,LTLAQWSPVI,AQWSPVIAAS,TQ ARSPSSAA,TQAKSPSPAT,AKSPSPATSV,RKQTKVLWPL,LS LPTRPRLL,EESLPGAMNA EGR2 c.1105G>A p.E369 SKTPVHERPYPCPAEGCDRRFSRSD[p.E RRFSRSDKL CLL K 369K]KLTRHIRIHTGHKPFQCRICMRNF SR EGR2 c.1169G>A p.R390 SRSDELTRHIRIHTGHKPFQCRICM[p.R RICMHNFSR,HNFSRSDHL,FQCRICMHNF,CMHNFSRSDH, CRC H 390H]HNFSRSDHLTTHIRTHTGEKPFA MHNFSRSDHL CDY EGR2 c.1189C>A p.H397 RHIRIHTGHKPFQCRICMRNFSRSD[p.H RNFSRSDNL,RSDNLTTHI,MRNFSRSDNL,FSRSDNLTTH,SR CLL N 397N]NLTTHIRTHTGEKPFACDYCGRK SDNLTTHI FAR EHD3 c.130G>A p.E44K QTVSEGLKKLYKSKLLPLEEHYRFH[p.E4 HYRFHKFHS,RFHKFHSPA,FHKFHSPAL,EEHYRFHKF,YRFH CRC 4K]KFHSPALEDADFDNKPMVLLVGQY KFHSP,RFHKFHSPAL,YRFHKFHSPA,LEEHYRFHKF,EEHYRF ST HKFH EHHA c.2112G>T p.Q704 LQKYYRQNPDIPQLEPSDYLKKLAS[p.Q ASHGNPPLK,LASHGNPPL,KLASHGNPPL,LASHGNPPLK LUAD DH H 704H]HGNPPLKEWQSLAGSPSSKL* EIF1A c.26G>A p.G9D MPKNKGKG[p.G9D]DKNRRRGKNENE KGDKNRRRGK THCA X SEKRELVFKEDGQE EIF2C c.416G>A p.R139 EVTIPGEGKDRIFKVSIKWLAIVSW[p.R1 WLAIVSWQM,WQMLHEALV,AIVSWQMLH,SWQMLHEA CRC 1 Q 39Q]QMLHEALVSGQIPVPLESVQALD L,LAIVSWQML,WLAIVSWQML,IVSWQMLHEA,KWLAIVS VAM WQM,SWQMLHEALV,VSWQMLHEAL,WQMLHEALVS EIF3J c.23C>G p.A8G MAAAAAA[p.A8G]GGDSDSWDADAF AAAGGDSDSW TGCT SVEDPVRKVGGGGT EIF4G c.23G>A p.R8H MNSQPQT[p.R8H]HSPFFQRPQIQPPR QTHSPFFQR,SQPQTHSPF,QPQTHSPFF,SQPQTHSPFF,NS CLL 3 ATIPNSSPSIRP QPQTHSPF ELAVL c.789G>T p.L263 RLDNLLNMAYGVKRFSPMTIDGMTS[p. MTIDGMTSF,TIDGMTSFA,DGMTSFAGI,MTSFAGINI,MTI LUAD 2 F L263F]FAGINIPGHPGTGWCIFVYNLA DGMTSFA,GMTSFAGINI,PMTIDGMTSF PDAD ELF3 c.915de|C p.F305 DILIHPELNEGLMKWENRHEGVFKF[p. GVFKFCAPR,RLWPNYGAK,VFKFCAPRL,CAPRLWPNY,YG CRC fs F305fs]CAPRLWPNYGAKRKRTAT* AKRKRTA,FKFCAPRLW,HEGVFKFCA,RLWPNYGAKR,VFK FCAPRLW,FCAPRLWPNY,EGVFKFCAPR,APRLWPNYGA,G VFKFCAPRL ELF4 c.1244C>T p.S415 KLTKAVSASSVPSNIHLGVAPVGSG[p.S GLALTLQTI,GVAPVGSGL,APVGSGLAL,VGSGLALTL,GVAP HNSC L 415L]LALTLQTIPLTTVLTNGPPASTTAP VGSGLA,LGVAPVGSGL,SGLALTLQTI,LALTLQTIPL T ELMO c.422C>T p.T141 RKRPYDSDNLQHEELLMKLWNLLMP[p. KLWNLLMPM,LWNLLMPMK,MPMKKLNAR,LLMPMKKL CRC D2 M T141M]MKKLNARISKQWAEIGFQGD NA,KLWNLLMPMK,LWNLLMPMKK,MKKLNARISK,LMP DPKTDF MKKLNAR,MPMKKLNARI,MKLWNLLMPM EME1 c.1708G>C p.D570 IGPELSRRIYLQMTTLQPHLSLDSA[p.D5 QPHLSLDSAH LUSC H 70H]H* EMILI c.79C>G p.R27G APRTLWSCYLCCLLTAAAGAASYPP[p.R SYPPGGFSL,YPPGGFSLY,AASYPPGGF,SYPPGGFSLY,ASYP BLCA N1 27G]GGFSLYTGSSGALSPGGPQAQIAP PGGFSL,GAASYPPGGF RP EML6 c.2414A>G p.K805 FSADGKCLVSVGLDDFHSIVFWDWK[p. SIVFWDWKR,WDWKRGEKI,HSIVFWDWKR,VFWDWKRG TGCT R K805R]RGEKIATTRGHKDKIFVVKCNP EK HHVD EMR1 c.1478G>A p.R493 EESESTETTGVAFVSFVGMESVLNE[p.R SVLNEHFFK,MESVLNEHF,ESVLNEHFFK,HFFKDHQAPL,G LUAD H 493H]HFFKDHQAPLTTSEIKLKMNSRV MESVLNEHF,MESVLNEHFF,NEHFFKDHQA VGG EMR1 c.1892G>A p.R631 SHVGIIISLVCLVLAIATFLLCRSI[p.R SIQNHNTYL,RSIQNHNTY,IQNHNTYLH,QNHNTYLHL,RSI UCEC Q 631Q]QNHNTYLHLHLCVCLLLAKTLFLAGI QNHNTYL,IQNHNTYLHL,CRSIQNHNTY EMR2 c.224C>T p.S75L GFSSFSEIITTPMETCDDINECATL[p.S7 TLLKVSCGK,DINECATLL,LLKVSCGKF,NECATLLKV,ATLLKV CRC 5L]LKVSCGKFSDCWNTEGSYDCVCSPG SCGK,DINECATLLK,TLLKVSCGKF Y ENAH c.1541G>T p.R514 TPEPTRKPWERTNTMNGSKSPVISR[p. VISRLDSPR,ISRLDSPRK,SKSPVISRL,VISRLDSPRK, LUAD L R514L]LDSPRKNQIVFDNRSYDSLHRPK GSKSPVISRL,PVISRLDSPR STP ENAM c.1118G>A p.R373 PFYRNQQVQRGPRWNFFAWERKQVA QVAHPGNPV,VAHPGNPVY,KQVAHPGNPV,QVAHPGNP CRC H [p.R373H]HPGNPVYHKAYPPTSRGNY VY,FAWERKQVAH PNYAGNP ENOX c.1066C>T p.R356 QFEQIVAVYHSASKQKAWDHFTKAQ[p. AQWKNISVW,KAQWKNISV,HFTKAQWKNI,QWKNISVW CRC 2 W R356W]WKNISVWCKQAEEIRNIHND CK,KAQWKNISVW,AQWKNISVWC ELMGIR ENPEP c.866T>G p.F289 EESVDDKWTRTTFEKSVPMSTYLVC[p. STYLVCCAV,MSTYLVCCA,CAVHQFDSV,LVCCAVHQF,YLV KIRC C F289C]CAVHQFDSVKRISNSGKPLTIYV CCAVHQF,MSTYLVCCAV,CAVHQFDSVK QPE ENPP1 c.2213G>A p.G738 YQDFRIPLSPVHKCSFYKNNTKVSY[p.G NTKVSYEFL,YEFLSPPQL,SYEFLSPPQL,EFLSPPQLNK,KNN LUAD E 738E]EFLSPPQLNKNSSGIYSEALLTTNI TKVSYEF,YEFLSPPQLN V ENTP c.611de|G p.G204 NFIKYGWVGRWFRPRKGTLGAMDLG[p. TLGAMDLGV,SLLRQPVQL,WLGTLWPSL,TLWPSLPSS,STL STAD D2 fs G204fs]VPLPRSLLRQPVQLRTEPARS WTFCGL,AVTPTSAEI,ASSAMAVTR,TLWTFCGLR,LWTFCG SCISTASTTESTPTASSAMAVTRSSRGC LRW,RSLLRQPVQ,LLRQPVQLR,AMAVTRSSR,RSSRGCWP WPAPSRPTASTPAGRGAFPPKCCSGM A,SSRGCWPAP,RGCWPAPSR,AGRGAFPPK,HAPWPSGPR, CTSHHAPWPSGPRTSTAVPGSACQGA STTESTPTA,ESTPTASSA,STPTASSAM,EIWFLGSSA,WPAP VTPTSAEIWFLGSSASPPAPSPDALSMG SRPTA,APSRPTAST,RPTASTPAG,FPPKCCSGM,WPSGPRT SSSPQWLGTLWPSLPSSTLWTFCGLRW ST,APSPDALSM,WPSLPSSTL,LPSSTLWTF,GAMDLGVPL,L GCPWPPCSSWRQPQ* GVPLPRSL,ARSSCISTA,MCTSHHAPW,SMGSSSPQW,CGL RWGCPW,TPTSAEIWF,SPQWLGTLW,CPWPPCSSW,AEI WFLGSS,GTLGAMDLGV,FLGSSASPPA,SMGSSSPQWL,TL WPSLPSST,AMDLGVPLPR,SAMAVTRSSR,STLWTFCGLR, QWLGTLWPSL,LWPSLPSSTL,SLPSSTLWTF,RSLLRQPVQL, RTEPARSSCI,RSSCISTAST,SSRGCWPAPS,RTSTAVPGSA,S LLRQPVQLR,TASSAMAVTR,HHAPWPSGPR,STPTASSAM A,SAEIWFLGS,SSTLWTFCGL,WTFCGLRWGC,LPRSLLRQ PV,QPVQLRTEPA,TPTASSAMAV,WPAPSRPTAS,WPSGPR TSTA,VPGSACQGAV,SPPAPSPDAL,ASTPAGRGAF,ESTPT ASSAM,LSMGSSSPQW,LGAMDLGVPL,GMCTSHHAPW,C QGAVTPTSA,AEIWFLGSSA,SSSPQWLGTL,TPTSAEIWFL, WPSLPSSTLW,TESTPTASSA,LPSSTLWTFC ENTP c.979G>A p.E327 HTEHVYRVYVTTFLGFGGNFARQRY[p. GNFARQRYK,RQRYKDLVL,FARQRYKDL,KDLVLNETL,GGN CRC D7 K E327K]KDLVLNETLNKNRLLGQKTGLSP FARQRYK,RQRYKDLVLN,FARQRYKDLV,YKDLVLNETL DNP EOME c.995de|G p.G332 LNPTAHYNVFVEVVLADPNHWRFQG[p. HWRFQGANG STAD S fs G332fs]ANG* EP300 c.3491G>A p.C116 YKYCSKLSEVFEQEIDPVMQSLGYC[p.C SLGYCYGRK,YCYGRKLEF,VMQSLGYCY,QSLGYCYGR,LGY HNSC 4Y 1164Y]YGRKLEFSPQTLCCYGKQLCTIP CYGRKL,QSLGYCYGRK,GYCYGRKLEF,PVMQSLGYCY,MQ RDA SLGYCYGR EP300 c.4195G>A p.D139 FGMHVQEYGSDCPPPNQRRVYISYL[p. YLNSVHFFR,NSVHFFRPK,VYISYLNSV,ISYLNSVHF,SYLNSV CESC,HNSC, 9N D1399N]NSVHFFRPKCLRTAVYHEILIG HFF,RVYISYLNS,YISYLNSVH,RVYISYLNSV,SYLNSVHFFR, LUSC YLEY YISYLNSVHF,ISYLNSVHFF,LNSVHFFRPK EPB41 c.2686G>T p.A896 SYSAGDSGDAAAQPAFTGIKGKEGS[p. GSSLTEGAK,IKGKEGSSL,KEGSSLTEGA LUAD L3 S A896S]SLTEGAKEEGGEEVAKAVLEQE ETAA EPG5 c.1105G>A p.D369 KVFSYHRYQRVEMNENALVELKKLF[p. KLFNAKSEH,ELKKLFNAK,VELKKLFNA,KLFNAKSEHL CRC N D369N]NAKSEHLHQTLALHSYTSVLSRL QVE EPG5 c.6866G>T p.R228 MALSSLFMEVLMMMNNATIPTAEFL[p. LLGSIRTWI,TIPTAEFLL,FLLGSIRTW,FLLGSIRTWI,EFLLGSI LUAD 9L R2289L]LGSIRTWIGQKMHGLVVLPLL RTW,ATIPTAEFLL,AEFLLGSIRT TAACQ EPHA c.332G>T p.G111 IYRGEEASRVHVELQFTVRDCKSFP[p.G FPVGAGPLG,TVRDCKSFPV,KSFPVGAGPL,FPVGAGPLGC LUAD 1 V 111V]VGAGPLGCKETFNLLYMESDQD VGIQ EPHA c.550G>A p.A184 LVSGSVKLNVERCSLGRLTRRGLYL[p.A YLTFHNPGA,LTRRGLYLT,TRRGLYLTF,LTFHNPGACV,LTRR GBM 1 T 184T]TFHNPGACVALVSVRVFYQRCPE GLYLTF TLN EPHA c.2604de|C p.P868 ERPYWDMSGQDVIKAVEDGFRLPPP[p. RLPPPGTVL,GFRLPPPGTV,LPPPGTVLTF,FRLPPPGTVL STAD 10 fs P868fs]GTVLTFCTD* EPHA c.1379de|C p.P460 NQTEPPKVRLEGRSTTSLSVSWSIP[p.P ATMCAAPRV,LSVSWSIPR,SVSWSIPRR,GSTRSLTAR,RSRA STAD 2 fs 460fs]RRSRAECGSTRSLTARRETPTAT ECGST,STRSLTARR,RSLTARRET,TARRETPTA,SWSIPRRSR, MCAAPRVSP* TATMCAAPR,ETPTATMCA,IPRRSRAEC,TPTATMCAA,AE CGSTRSL,RRETPTATM,RETPTATMC,SLSVSWSIPR,LSVS WSIPRR,SWSIPRRSRA,RSRAECGSTR,VSWSIPRRSR,PTAT MCAAPR,ETPTATMCAA,TATMCAAPRV,RAECGSTRSL,AR RETPTATM,RETPTATMCA,AECGSTRSLT EPHA c.2405C>G p.T802 AAYTTRGGKIPIRWTSPEAIAYRKF[p.T8 RSASDVWSY,KFRSASDVW,IAYRKFRSA,AYRKFRSAS,EAIA HNSC 3 R 02R]RSASDVWSYGIVLWEVMSYGERP YRKFR,RKFRSASDV,AIAYRKFRSA,KFRSASDVWS,IAYRKFR YWE SAS,RKFRSASDVW,FRSASDVWSY EPHA c.2854G>C p.D952 TTGGKIPIRWTAPEAIAYRKFSSAS[p.D9 SSASHAWSY,KFSSASHAW,ASHAWSYGI,HAWSYGIVM,Y HNSC 6 H 52H]HAWSYGIVMWEVMSYGERPYW RKFSSASH,RKFSSASHA,FSSASHAWSY,AYRKFSSASH,ASH EMSNQ AWSYGIV,SASHAWSYGI,RKFSSASHAW,SHAWSYGIVM, HAWSYGIVMW EPHB2 c.1175G>A p.R392 SGRGACTRCGDNVQYAPRQLGLTEP[p. GLTEPHIYI,RQLGLTEPH,LGLTEPHIY,RQLGLTEPHI,QLGLT CRC H R392H]HIYISDLLAHTQYTFEIQAVNGV EPHIY,HIYISDLLAH,TEPHIYISDL TDQ EPHB6 c.1010G>A p.R337 KACQACPRGLYKSSAGNAPCSPCPA[p. HSHAPNPAA LUAD H R337H]HSHAPNPAAPVCPCLEGFYRAS SDPP EPHB6 c.160de|G p.G54 ALEEVLLDTTGETSEIGWLTYPPGG[p.G LTYPPGGGTR STAD fs 54fs]GTR* EPHX1 c.394de|C p.P132 ILNRYPHFKTKIEGLDIHFIHVKPP[p.P13 KPPSCPQAI,HVKPPSCPQA,CPQAIPRSPC STAD fs 2fs]SCPQAIPRSPC* EPHX4 c.845G>A p.R282 TTEDLEAYIYVFSQPGALSGPINHY[p.R2 HYQNIFSCL,GPINHYQNI,YQNIFSCLP,QNIFSCLPL,YQNIFS UCEC Q 82Q]QNIFSCLPLKHHMVTTPTLLLWGE CLPL,QNIFSCLPLK,GPINHYQNIF,NHYQNIFSCL ND EPPK1 c.6044de|G p.G201 FQAMQKQLIEKAEALRLLEVQVATG[p. STTTGSHWK,AVCTRTSMR,TSMRSFPTR,CTRTSMRSF,RTS STAD 5fs G2015fs]VSSTHSTTTGSHWKQPTDGA MRSFPT,SMRSFPTRS,LEVQVATGV,VQVATGVSS,HSTTTG VCTRTSMRSFPTRST* SHW,WKQPTDGAV,GAVCTRTSM,LLEVQVATGV,RTSMR SFPTR,HSTTTGSHWK,STHSTTTGSH,CTRTSMRSFP,SMRS FPTRST,VQVATGVSST,VCTRTSMRSF EPPK1 c.7132G>C p.D237 HSHRVPVDVAYRRGYFDEEMNRVLA[p. EEMNRVLAH,HPSDDTKGF,VLAHPSDDTK,HPSDDTKGFF, ACC 8H D2378H]HPSDDTKGFFDPNTHENLTY DEEMNRVLAH LQLLQR EPRS c.3451G>T p.V115 MYPAYAKWVQSHRDLPIKLNQWCNV[p. KLNQWCNVL,CNVLRWEFK,NQWCNVLRW,LNQWCNVLR, LUAD 1L V1151L]LRWEFKHPQPFLRTREFLW WCNVLRWEF,KLNQWCNVLR,QWCNVLRWEF,IKLNQW QEGHSAF CNVL EPRS c.4003C>A p.L133 GITNALSEEDKEALIAKCNDYRRRL[p.L1 RLISVNIRV,RRRLISVNI,DYRRRLISV,RRRLISVNIR,RLISVNI TGCT 5I 335I]ISVNIRVRADLRDNYSPGWKFNH RVR,NDYRRRLISV,YRRRLISVNI WEL ERBB2 c.2264T>C p.L755 AFGTVYKGIWIPDGENVKIPVAIKV[p.L VSRENTSPK,IPVAIKVSR,KVSRENTSPK,VSRENTSPKA BRCA S 755S]SRENTSPKANKEILDEAYVMAGV GSP ERBB2 c.2305G>T p.D769 ENVKIPVAIKVLRENTSPKANKEIL[p.D7 ILYEAYVMA,YEAYVMAGV,NKEILYEAY,KEILYEAYV,EILYE BRCA YV 69Y]YEAYVMAGVGSPYVSRLLGICLTSTV AYVM,ILYEAYVMAG,ANKEILYEAY,EILYEAYVMA,KEILYEA YVM,SPKANKEILY,YEAYVMAGVG ERBB2 c.2310_2311 p.774_ AIKVLRENTSPKANKEILDEAYVMA[p.7 VMAYVMAGV,YVMAYVMAG,DEAYVMAYV,EAYVMAYV LUAD insGCATA 775ins 74_775insAYVM]YVMAGVGSPYVSRL M,LDEAYVMAY,MAYVMAGVG,ILDEAYVMAY,YVMAYV CGTGATG AYVM LGICLTSTVQLVTQLMPYGCLLD MAGV,EAYVMAYVMA,DEAYVMAYVM ERBB2 c.2326_232 p.776_ AIKVLRENTSPKANKEILDEAYVMA[p.7 AVCVGSPYV,MAVCVGSPY,EAYVMAVCV,YVMAVCVGS,D LUAD 7insTCT 776G> 76_776G>VC]VCVGSPYVSRLLGICLTS EAYVMAVC,ILDEAYVMAV,MAVCVGSPYV,VMAVCVGSP VC TVQLVTQLMP Y,DEAYVMAVCV ERBB2 c.2524G>A p.V842I LGSQDLLNWCMQIAKGMSYLEDVRL[p. RLIHRDLAA,SYLEDVRLI,LIHRDLAAR,RLIHRDLAAR,YLEDV CRC V842I]IHRDLAARNVLVKSPNHVKITDF RLIHR,MSYLEDVRLI GLA ERBB2 c.2748G>A p.M91 LESILRRRFTHQSDVWSYGVTVWEL[p. YGVTVWELI,VTVWELITF,LITFGAKPY,WELITFGAK,TVWE HNSC 6I M916I]ITFGAKPYDGIPAREIPDLLEKGE LITFGA,SYGVTVWELI,ELITFGAKPY,GVTVWELITF,WELITF RL GAKP ERBB2 c.929C>A p.S310 PEGRYTFGASCVTACPYNYLSTDVG[p.S YLSTDVGYC,STDVGYCTLV,YLSTDVGYCT,YNYLSTDVGY,L LUAD Y 310Y]YCTLVCPLHNQEVTAEDGTQRCE STDVGYCTL,VGYCTLVCPL KCS ERBB2 c.929C>T p.S310 PEGRYTFGASCVTACPYNYLSTDVG[p.S STDVGFCTL,YLSTDVGFC,NYLSTDVGF,STDVGFCTLV,YLST BLCA,BRCA, F 310F]FCTLVCPLHNQEVTAEDGTQRCE DVGFCT,YNYLSTDVGF,LSTDVGFCTL,VGFCTLVCPL CESC,STAD KCS ERBB3 c.273G>A p.M91I VLTGHNADLSFLQWIREVTGYVLVA[p. YVLVAINEF,VAINEFSTL,INEFSTLPL,AINEFSTLPL,GYVLVAI BLCA M91I]INEFSTLPLPNLRVVRGTQVYDG NEF,EVTGYVLVAI KFA ERBB3 c.310G>A p.V104 WIREVTGYVLVAMNEFSTLPLPNLR[p. RMVRGTQVY,LPLPNLRMV,LRMVRGTQV,TLPLPNLRMV, CESC,CRC, M V104M]MVRGTQVYDGKFAIFVMLNY NLRMVRGTQV,LRMVRGTQVY STAD NTNSSH ERBB3 c.310G>T p.V104 WIREVTGYVLVAMNEFSTLPLPNLR[p. RLVRGTQVY,LPLPNLRLV,TLPLPNLRLV,NLRLVRGTQV,LRL BLCA L V104L]LVRGTQVYDGKFAIFVMLNYNT VRGTQVY NSSH ERBB3 c.889G>T p.D297 LEPNPHTKYQYGGVCVASCPHNFVV[p. FVVYQTSCV,VVYQTSCVR,YQTSCVRAC,ASCPHNFVVY,FV BLCA Y D297Y]YQTSCVRACPPDKMEVDKNGL VYQTSCVR KMCEP ERC1 c.2075A>G p.K692 DLSEKEASLLDLKEHASSLASSGLK[p.K6 GLKRDSRLK,SLASSGLKR,SSLASSGLKR,SGLKRDSRLK,LKR TGCT R 92R]RDSRLKTLEIALEQKKEECLKMESQ DSRLKTL L ERCC2 c.41A>G p.Y14C MKLNVDGLLVYFP[p.Y14C]CDYIYPEQ LVYFPCDYI,VYFPCDYIY,LLVYFPCDY,CDYIYPEQF,FPCDYIY BLCA FSYMRELKRTLDAKGHGV PE,LLVYFPCDYI,LVYFPCDYIY,GLLVYFPCDY ERCC2 c.713A>G p.N238 LDPKIADLVSKELARKAVVVFDEAH[p.N VVFDEAHSI,EAHSIDNVCI BLCA S 238S]SIDNVCIDSMSVNLTRRTLDRCQ GNL ERCC2 c.934G>A p.D312 RLVEGLREASAARETDAHLANPVLP[p. NPVLPNEVL,LPNEVLQEA,VLPNEVLQEA,LANPVLPNEV,LP ACC N D312N]NEVLQEAVPGSIRTAEHFLGFL NEVLQEAV RRLL ERCC6 c.2338G>A p.V780I SLPDKNEQVLFCRLTDEQHKVYQNF[p. FIDSKEVYR,NFIDSKEVY,YQNFIDSKEV,FIDSKEVYRI,KVYQ CRC V780I]IDSKEVYRILNGEMQIFSGLIALR NFIDSK,NFIDSKEVYR,QNFIDSKEVY KI ERCC6 c.1514G>A p.R505 LVFSQSRQILNIIERLLKNRHFKTL[p.R50 KTLQIDGTV,LQIDGTVTH,LQIDGTVTHL,KNRHFKTLQI CRC L Q 5Q]QIDGTVTHLLEREKRINLFQQNKDY S ERCC6 c.1333C>A p.L445I LGDTSILDDLFKSHGNSPTQLPKKV[p.L KVISGPMEK,VISGPMEKAK,SPTQLPKKVI,LPKKVISGPM UCEC L2 445I]ISGPMEKAKQRPKDFWDILNEQN DES ERN2 c.884C>A p.T295 TQDLGVPVMGVYTWHQDGLRQLPHL[p. GLRQLPHLK,KLARDTLFIF,RQLPHLKLA,QLPHLKLAR,HLKL LUAD K T295K]KLARDTLHFLALRWGHIRLPA ARDTL,KLARDTLHFL,RQLPHLKLAR,LKLARDTLHF SGPRD ERRFI c.1261G>A p.A421 LLPERPPYLDKYEKFFREAEETNGG[p.A AEETNGGTQI CRC 1 T 421T]TQIQPLPADCGISSATEKPDSKTK MD ESCO1 c.899G>A p.R300 TLPKSPQPSVPEQSDNELEQAGKSK[p.R KSKQGSILQ,GKSKQGSIL,SKQGSILQL,KSKQGSILQL CRC Q 300Q]QGSILQLCEEIAGEIESDNVEVKK ES ESF1 c.295de|A p.T99fs LSDSDSNLSGEDSKALSQKKIKKKK[p.T9 RLKKKSIQK,KIKKKKPRL,KKKKPRLKK,KKKPRLKKK,KPRLKK STAD 9fs]PRLKKKSIQKI* KSI,LKKKSIQKI,RLKKKSIQKI,KIKKKKPRLK,KKKKPRLKKK ESPN c.1286_134 p.PPPP QSYMDMLNPELGLPRGTIGKPTPPP[p. IGKPTPPPGY,KPTPPPGYPA PAAD 8de|CACCC PPSFPP PPPPPPSFPPPPPPPGTQLPP430de|]G CCACCACC PPPPP YPAPKPPVGPQAADIYMQTKNKLRHVE CCCACCCA GTQLP TEALKKELSSCDGHDGLRRQDSSRKPRA GCTTCCCCC P430de| FSKQPSTGDYYRQLGRCPGETLAARPG CGCCACCC MAHSE CCGCCCCC AGGCACCC AACTGCCC C ESPNP c.1880G>A p.R627 EEEQRWKEEEEARLASMPAWRWDLL[p. AWRWDLLQK,AWRWDLLQKK,WRWDLLQKKL GBM Q R627Q]QKKLEEE ESPNP c.191_198d p.H64fs PLYLACQEGHLEVTQYLVQECGADP[p. GQRRRHRHA,RRRHRHALR,RPRRHDPTA,GPQPGHRVV,Q PAAD e|ACGCGCG H64fs]RPRRHDPTARRGADGPQPGHR RRRHRHAL,RPQQGAQLA,AAAARRGDL,QQGAQLAAA,GE C VVGELHRREPVGAGQRRRHRHALRGE LHRREPV,GQRRRHRHAL,LVQECGADPR,QPGHRVVGEL,E PRPQQGAQLAAAARRGDLG* PRPQQGAQL,RPQQGAQLAA,LAAAARRGDL,QQGAQLAA AA ESPNP c.888_950d p.296_ QSYMDMLNPELGLPWGTIGKPIPPP[p. IGKPIPPPSY PAAD e|ACCCCCA 317PPP 296_317PPPPSFPPPPPPPGTQLPPPPP CCCAGCTT PSFPPP >P]SYPSPKPPVGPQAADIYMQTKNKLR CCCCCCGC PPPPG HVETEALKKEPSSCDGHDGLRRQDSSR CACCCCCG TQLPPP KPRAFSKQPSTGDYYRQLGRCPGETLV CCCCCAGG PP>P ARPGMAHRE CACCCAAC TGCCCCCA CCCCCACC ESRRA c.655G>A p.D219 VNALVSHLLVVEPEKLYAMPDPAGP[p. GPNGHLPAV,MPDPAGPNGH HNSC N D219N]NGHLPAVATLCDLFDREIWTIS WAK ESYT1 c.2446C>T p.R816 LQVNSLIQTQKSAELAAALLSIYME[p.R LLSIYMEWA,ALLSIYMEW,IYMEWAEDL,EWAEDLPLR,ME BRCA W 816W]WAEDLPLRKGTKHLSPYATLTV WAEDLPL,ALLSIYMEWA,YMEWAEDLPL,AALLSIYMEW GDSS ESYT3 c.1721C>T p.S574 QILPYADLTLEQRFQLDHSGLDSLI[p.S5 SLIFMRLVL,FMRLVLRFL,LIFMRLVLR,IFMRLVLRF,DSLIFM LUSC F 74F]FMRLVLRFLQVEERELGSPYTGPEA RLV,HSGLDSLIF,SGLDSLIFM,GLDSLIFMRL,SLIFMRLVLR,I L FMRLVLRFL,SGLDSLIFMR,LIFMRLVLRF,HSGLDSLIFM ETFDH c.841A>T p.I281F LYKKFDLRANCEPQTYGIGLKELWV[p.I WVFDEKNWK,IGLKELWVF CLL 281F]FDEKNWKPGRVDHTVGWPLDR HTYGG ETV6 c.1105C>T p.R369 YVYQLLSDSRYENFIRWEDKESKIF[p.R3 WIVDPNGLA,KESKIFWIV,IFWIVDPNGL CRC W 69W]WIVDPNGLARLWGNHKNRTNM TYEKM EXOC c.1762C>T p.R588 QHNCGTPLPVSSEKDMIRQMMIKIF[p. MMIKIFCCI,RQMMIKIFC,QMMIKIFCCI,KIFCCIEPEL,RQM UCEC 1 C R588C]CCIEPELNNLIALGDKIDSFNSLY MIKIFCC ML EXOSC c.32G>C p.R11P MAMEMRLPVA[p.R11P]PKPLSERLGR EMRLPVAPK,APKPLSERL,MEMRLPVA,MEMRLPVAPK, KIRP 2 DTKKHLWPGDTITTD MRLPVAPKPL EXOSC c.480de|A p.L160f CDLICLDYDGNILDACTFALLAALK[p.L1 KMYSCLKLL,ALKMYSCLK,ALLAALKMY,FALLAALKM,AALK STAD 8 s 60fs]MYSCLKLL* MYSCL,LKMYSCLKL,LLAALKMYSC,ALKMYSCLKL,AALKM YSCLK,LAALKMYSCL,FALLAALKMY,LKMYSCLKLL EZH2 c.1529A>G p.K510 VDTPPRKKKRKHRLWAAHCRKIQLK[p. RDGSSNHVY,LKRDGSSNH,KRDGSSNHVY TGCT R K510R]RDGSSNHVYNYQPCDHPRQPC DSSCP EZH2 c.1922A>T p.Y641 LAPSDVAGWGIFIKDPVQKNEFISE[p.Y FISEFCGEI,QKNEFISEF,SEFCGEIIS,FISEFCGEII,VQKNEFIS DLBCL F 641F]FCGEIISQDEADRRGKVYDKYMC EF SFL F10 c.349G>A p.E117 TSPCQNQGKCKDGLGEYTCTCLEGF[p. KGKNCELFT,FKGKNCELF,YTCTCLEGFK,CTCLEGFKGK,GFK UCEC K E117K]KGKNCELFTRKLCSLDNGDCDQ GKNCELF,KGKNCELFTR FCHE F5 c.1277A>T p.Q426 DESFTKHTVNPNMKEDGILGPIIRA[p.Q ILGPIIRAL,ALVRDTLKI,LVRDTLKIV,RALVRDTLK,IRALVRD LIHC L 426L]LVRDTLKIVFKNMASRPYSIYPHG TL,ILGPIIRALV,ALVRDTLKIV,IIRALVRDTL,RALVRDTLKI,LV VT RDTLKIVF F5 c.3995T>C p.L133 LSQTNLSPALGQMPISPDLSHTTLS[p.L TLSPDFSQT,SPDFSQTNL,SHTTLSPDF,LSHTTLSPDF CLL 2P 1332P]PDFSQTNLSPELSQTNLSPALG QMPL F8 c.6806C>A p.S226 NPKEWLQVDFQKTMKVTGVTTQGVK[p. YLLTSMYVK,KYLLTSMYV,GVKYLLTSM,GVTTQGVKY,VKY CRC 9Y S2269Y]YLLTSMYVKEFLISSSQDGH LLTSMY,TTQGVKYLL,KYLLTSMYVK,GVKYLLTSMY,QGVKY QWTLFF LLTSM,VKYLLTSMYV FAM1 c.223G>C p.D75H SSSRINIPERASGPEGNLNQIVTEP[p.D7 HANFPQFLH,EPHANFPQF,IVTEPHANF,EPHANFPQFL,QI TGCT 04B 5H]HANFPQFLHEGLSKPVYVINWFMS VTEPHANF,EPHANFPQF FG FAM1 0.376C>A p.H126 AREWKGETPRNKLMRKAYEELFWRH[p. ELFWRHNIK,NIKCVRQVR,EELFWRHNI,FWRHNIKCVR,H KIRC 05A N H126N]NIKCVRQVRRDNYDALRSVL NIKCVRQVR,NIKCVRQVRR,YEELFWRHNI FQIFSQ FAM1 c.466_474d p.GGG LSRASFDYLRLVVRELEQQLAAVRG[p.G QLAAVRGMA,LAAVRGMAL,QQLAAVRGM,QLAAVRGM ACC 09A e|GGGGGT 156de| GG156de|]MALPQPQPQSLPLPPSLPS AL,EQQLAAVRGM,QQLAAVRGMA GGC ALAPVPSLPSAPAPV FAM1 c.807de|A p.S269f KIYGKQSMVDEVSGKVLEMDISKKK[p. KLNRMKVPL,PLMKLITRV,RMKVPLMKL,ISKKKHYNR,SKK PRAD 11B s S269fs]HYNRKISIKKLNRMKVPLMKLIT KHYNRK,KHYNRKISI,HYNRKISIK,YNRKISIKK,KISIKKLNR,SI RV* KKLNRMK,LNRMKVPLM,ISIKKLNRM,MKVPLMKLI,KLNR MKVPLM,RMKVPLMKLI,ISIKKLNRMK,ISKKKHYNRK,KHY NRKISIK,HYNRKISIKK,KISIKKLNRM,SIKKLNRMKV,LNRM KVPLMK,KVPLMKLITR,DISKKKHYNR,KKHYNRKISI,KKLNR MKVPL,VPLMKLITRV FAM1 c.1322de|T p.L441f IKQLQKGVQQKRPSEAQSVILRRYF[p.L SVILRRYFW STAD 16A s 441fs]WN* FAM1 c.1400C>A p.P467 DSEPRQEVPMYTGSEPRQEVPMYTG[p. HESRQEVPM,VPMYTGHES,RQEVPMYTGH,HESRQEVPM LUAD 20B H P467H]HESRQEVPMYTGPESRQEVLI Y RTDPE FAM1 c.1145G>A p.R382 LSSQPIGTKPSSSSQRGSLRKVATG[p.R3 KVATGHSAK,ATGHSAKDK,RKVATGHSA GBM 26B H 82H]HSAKDKETASAIKSSESPRDSVVRK Q FAM1 c.156C>A p.F52L IPFPETFDGDTDRLPEFIVQTSSYM[p.F5 VQTSSYMLV,MLVDENTFS,YMLVDENTF,FIVQTSSYML,IV LUAD 27C 2L]LVDENTFSNDALKVTFLITRLTGPAL QTSSYMLV,SYMLVDENTF FAM1 c.1933A>C p.S645 KGIDQEGKMVLLSLKLTPSEPCDPL[p.S LRSTLREPL,EPCDPLRSTL STAD 35B R 645R]RSTLREPLDIRSSLKDSHTEEQEEL S FAM1 c.1942C>A p.L648 DQEGKMVLLSLKLTPSEPCDPLSST[p.L TMREPLDIR,LSSTMREPL,STMREPLDIR,EPCDPLSSTM LUSC 35B M 648M]MREPLDIRSSLKDSHTEEQEELS VLS FAM1 c.2651G>A p.R884 GHCLPDGRTENTPGVETKGLNLKIP[p.R GLNLKIPHV,HVIALENPR,LKIPHVIAL,GLNLKIPHVI,NLKIPH CRC 35B H 884H]HVIALENPRTRSLHRALEETPKG VIAL,KGLNLKIPHV MPK FAM1 c.720G>C p.W240C GYCKPTSSEGSFYITSENCMQHAHK[p. MQHAHKCHR,CMQHAHKCHR LUAD 35B W240C]CHRDLCLLLLHAYRGLRLHFLVI MRD FAM1 c.855G>T p.Q285 LVIMRDIPELPHTELEALAVEETLS[p.Q2 TLSHLCSEL,HLCSELQML,SHLCSELQM,ETLSHLCSEL,LAVE LUSC 35B H 85H]HLCSELQMLNNPEKIAEQISKDLA ETLSHL,LSHLCSELQM WL FAM1 c.351de|C p.P117f LEADVNVEGLGTANETGVPIMAHPP[p. IMAHPPLST,MAHPPLSTV,WTLCWALPK,TSRTSRQWA,RT STAD 51A s P117fs]LSTVTTHWSSGWTLCWALPKR SRQWAPP,TLCWALPKR,SNWTSRTSR,VPIMAHPPL,THW ASNWTSRTSRQWAPPWTSCGS* SSGWTL,SGWTLCWAL,TSRQWAPPW,RQWAPPWTS,WS SGWTLCW,IMAHPPLSTV,GWTLCWALPK,WTLCWALPKR, ASNWTSRTSR,HWSSGWTLCW,RTSRQWAPPW,TTHWSS GWTL,WSSGWTLCWA,MAHPPLSTVT,SSGWTLCWAL,W ALPKRASNW,RQWAPPWTSC,PPLSTVTTHW FAM1 c.284A>G p.Q95R KEHQQQQRQQQQQQQQQRQRQQQ RQRQQQQQR,RRRQQEPSW,RQRQQQQQRR TGCT 55A QQ[p.Q95R]RRRQQEPSWPALLASMG ESSPAAQAH FAM1 c.472G>A p.E158 VCGGVPEPTGLDAACTKLQSLQRLF[p.E RLFKPTTPA,LQSLQRLFK,KPTTPAPPL,LQRLFKPTT,KLQSL UCEC 55B K 158K]KPTTPAPPLRPPDSLSRAPAEFPS QRLFK,LQRLFKPTTP,RLFKPTTPAP,FKPTTPAPPL AK FAM1 c.495G>T p.K165 NDRPRQPAPGDGSKERMCGEELEDT[p. DTNDDPECGV CRC 69B N K165N]NDDPECGVEEEDAGLAGQPP GKLTRS FAM1 c.166G>A p.E56K DALQPGSTRVAKGWSQGVGEVTSTS[p. STSKYCSCV,GEVTSTSKY,SKYCSCVSS,GVGEVTSTSK,VGEV CRC 70A E56K]KYCSCVSSSRKLIHSGIQRIHRDS TSTSKY,TSTSKYCSCV,SKYCSCVSSS PQ FAM1 c.1375G>A p.D459 SYSPQKKEPSKAETEERVSMVKTRD[p. MVKTRDNFK,KTRDNFKIY,SMVKTRDNF,SMVKTRDNFK, CRC 71B N D459N]NFKIYNEDVSFLSVNQNNYSRN MVKTRDNFKI,KTRDNFKIYN,VSMVKTRDNF,VKTRDNFKIY PTQS FAM1 c.2491G>A p.A831 QVFDAFTPRLQDSNKKVNQWALESF[p. FTKMIPLLR,SFTKMIPLL,ESFTKMIPL,WALESFTKM,NQWA BRCA 79A T A831T]TKMIPLLRESLHPMLLSIIITVAD LESFTK,SFTKMIPLLR,ESFTKMIPLL,WALESFTKMI,LESFTK NL MIPL FAM1 c.326G>A p.R109 KAALDKSAPCRRSVDHRKYLQKQLK[p. KQLKHFSQK,YLQKQLKHF,KHFSQKYSR,QLKFIFSQKY,KYL CRC 81A H R109H]HFSQKYSRLPRGLPGRAAEPYL QKQLKHF,KQLKHFSQKY,RKYLQKQLKH,KHFSQKYSRL KRGS FAM1 c.2350C>T p.R784 RALGRQQASSQCPGDSKDHIIATEE[p.R EEWGGPGQA,EEWGGPGQAG,TEEWGGPGQA ACC 84B W 784W]WGGPGQAGSPPGAAGQGSGE GCGLWE FAM1 c.4667470 p.IPPQ LIPPQAQELGIPLTPQQVQALGIPL[p.IP VQALGIPLT,VQALGIPLTP KIRC 86A 2de|TCCCT AQELEI PQAQELEIPL1556de|]TPQQAQALGIP CCGCAGGC PL1556 LTPQQAQELGIPLTPQQAQELGIPLTPQ TCAGGAAT de| QAQAQGIPLTPQQAQALGISLT TGGAGATC CCTCTCA FAM1 c.152G>A p.C51Y PRKAKIRHPVASFFHLFFRVSAIIV[p.C51 IIVYLLCEL,YLLCELLSS,QIIVYLLCEL,IIVYLL ACC,KIRP, 8B2 Y]YLLCELLSSSFITCMVTIILLLSCDF CELL,YLLCELLSSS TGCT FAM1 c.1284_128 p.D428 NYRRRCACDDCSLSHILTCGIMDPP[p.D LTCGIMDPPR STAD 93A 5insC fs 428fs]RH* FAM1 c.1284de|C p.D428 NYRRRCACDDCSLSHILTCGIMDPP[p.D SLMTSTFTS,WILLLTILL,ILLRGARPV,VMMKMLHHC,MLH STAD 93A fs 428fs]SLMTSTFTSSHFKWILLLTILLRGA HCQPNL,GIMDPPSLM,FTSSHFKWI,LLTILLRGA,LQARGPA RPVCHLQARGPAPALPSQFSSTPGSSSQ PA,ALPSQFSST,TVARHQLFV,STFTSSHFK,HQLFWMMK, TVARHQLFVVMMKMLHHCQPNLLIFI MTSTFTSSH,GSSSQTVAR,TFTSSHFKW,SHFKWILLL,KWIL H* LLTIL,QTVARHQLF,HCQPNLLIF,CQPNLLIFI,SSHFKWILL,V ARHQLFW,LTILLRGAR,QARGPAPAL,TSTFTSSFIF,LMTST FTSS,FKWILLLTI,RGARPVCHL,SQFSSTPGS,SQTVARHQL, ARHQLFWM,RHQLFWMM,QLFWMMKM,MKMLHHC QP,KMLHHCQPN,TPGSSSQTV,PPSLMTSTF,LLLTILLRGA, TVARHQLFVV,KMLHHCQPNL,MLHHCQPNLL,SLMTSTFT SS,HLQARGPAPA,LQARGPAPAL,QLFVVMMKML,TSTFTS SHFK,TFTSSHFKWI,HFKWILLLTI,KWILLLTILL,SQTVARHQ LF,SSHFKWILLL,GARPVCHLQA,VARHQLFVVM,RHQLFVV MMK,MTSTFTSSHF,WILLLTILLR,LLTILLRGAR,FTSSHFKW IL,STPGSSSQTV,QTVARHQLFV,GPAPALPSQF,LMTSTFTS SH,HQLFVVMMKM,CGIMDPPSLM,STFTSSHFKW,FKWIL LLTIL,SQFSSTPGSS,ARHQLFVVMM,MKMLHHCQPN,HHC QPNLLIF,LPSQFSSTPG FAM1 c.404_421d p.EEEE IEEEEYLGKEGYLEEEEYLGKEEHL[p.EEE LGKEEHLGK,EEHLGKEGY,HLGKEGYLEK,KEEHLGKEGY,EE KIRC 94B e|AGGAGG YL135d EYL135de|]GKEGYLEKEDYIEEVDYLGK HLGKEGYL AAGAGTAT e| KAYLEEEEYLGKKSYLEEEKALE CTGG FAM1 c.415T>C p.Y139 EYLGKEGYLEEEEYLGKEEHLEEEE[p.Y1 EEHLGKEGY,HLGKEGYLEK,EEEHLGKEGY,EEHLEEEEHL,EE TGCT 94B H 39H]HLGKEGYLEKEDYIEEVDYLGKKAY HLGKEGYL L FAM2 c.336G>T p.L112 QQLKKIFQEYGTVGVSLHIGISLIS[p.L11 GISLISFGI,LISFGIFYM,ISFGIFYMV,SLISFGIFY,ISLISFGIF, LUAD 10B F 2F]FGIFYMVVSSGVDMPAILLKLGFKES SFGIFYMVV,HIGISLISF,ISLISFGIFY,SLISFGIFYM,LISFGI FYMV,ISFGIFYMW,LHIGISLISF,GISLISFGIF FAM2 c.124de|G p.A42fs GPSQPPVRQGALQGGLLMGYSPAGG[p. RYPSFPLRL,SFPLRLVPL,STRYPSFPL,RHPPGSTRY,MGYSP STAD 14B A42fs]RHPPGSTRYPSFPLRLVPLSLIG AGGR,YPSFPLRLV,SPAGGRHPP,RLVPLSLIG,FPLRLVPLS,S p* TRYPSFPLR,RYPSFPLRLV,GGRHPPGSTR,LMGYSPAGGR,S PAGGRHPPG,FPLRLVPLSL,MGYSPAGGRH,GRHPPGSTRY, GSTRYPSFPL,TRYPSFPLRL FAM2 c.106C>T p.P36S RGLGAAEMPGQGPGSDWTERSSSAE[p. RSSSAESPA,AESPAVAGT,RSSSAESPAV KIRP 16A P36S]SPAVAGTEGGGGGSAGYSCYQ NSKGS FAM2 c.3691C>T p.P123 DMDDIFSSGIQAKTTKPKSRSAQAA[p. ASEPRFEHK,KSRSAQAAS,SAQAASEPR,AQAASEPRF,SEP TGCT 1B 1S P1231S]SEPRFEHKVSNIFDDPLNAFGG RFEHKV,RSAQAASEPR,AASEPRFEHK,KSRSAQAASE,SAQ Q* AASEPRF FAM2 c.2070_207 p.P690f PGGRGPQGALQSPSAQKRGLSPSPS[p. VQEATSLWK,EATSLWKPI,SPSPSCQQV,QQVAEATSL,QV KIRC 2F 1de|TT s P690fs]CQQVQEATSLWKPIPC* QEATSLWK,CQQVQEATSL,QQVQEATSLW,QEATSLWKPI FAM2 c.2071_207 p.S691 SPGGRGPQGALQSPSAQKRGLSPSP[p.S691de] LSPSPPASK,RGLSPSPPA,GLSPSPPASK KIRC,PRAD 2F 3de|TCT de| PASKSKKRPLFGSPSPAEKTPHPGPGLR FAM3 c.26A>G p.K9R MEAYEQVQ[p.K9R]RGPLKLKGVAELG VQRGPLKLK,YEQVQRGPL,QVQRGPLKLK,EQVQRGPLKL TGCT 2A VTKRKKKKKDKDK FAM4 c.2218C>T p.R740 LQTKYLGRQWRKSNMKTMSAIYQKV[p. AIYQKVCHR,IYQKVCHRM,AIYQKVCHRM,CHRMNDDWA STAD 0B C R740C]CHRMNDDWAYGNDIDARP Y,SAIYQKVCHR WDFQAEEC FAM4 c.1247_124 p.H416 RPPGTDGWPATVNYYVTPVQPLLA[p. LLARAYPTW,LARAYPTWL,RAYPTWLPC,VQPLLARAY,LLA TGCT 6B 8AC>GT R H416R]RAYPTWLPCN* RAYPTWL,PVQPLLARAY FAM4 c.1114G>T p.G372 GSSLRSEPSETGVSRLRLAPPKTRR[p.G3 KTRRWSSLH,WSSLHAEPSK,KTRRWSSLHA,PPKTRRWSSL, LUSC 7A W 72W]WSSLHAEPSKTGVSHLSPEPPKTE RLAPPKTRRW VS FAM4 c.2069G>T p.R690 EDKFFSQEKYWGRKFHTPSNSYTAQ[p. NSYTAQLVK,YTAQLVKMK,SYTAQLVKM,YTAQLVKMKY,S LUAD 7A L R690L]LVKMKYGAWYLKPKLWKKLRS NSYTAQLVK,LVKMKYGAWY,TPSNSYTAQL,NSYTAQLVK DEPLI M,QLVKMKYGAW FAM4 c.1701G>T p.L567 QRGRIRYGPWYFEPKLGKKLRSDEP[p.L KLRSDEPFI,KKLRSDEPF,EPFIDPKPV,RSDEPFIDPK,FIDPKP LUAD 7B F 567F]FIDPKPVLEKPDEPDILDGLYGPIA VLEK,EPFIDPKPVL,GKKLRSDEPF,KKLRSDEPFI F FAM4 c.489G>T p.W16 GKDMPPDLLLQVLKQLDPERKLEDA[p. CARCEAREK,DACARCEAR,LEDACARCEA LUAD 7B 3C W163C]CARCEAREKTTEVPTESGKYPC GESC FAM4 c.1162C>T p.P388 VSPLRQLPPEAGVSHLCPEPPKTRV[p.P KTRVSPLRP,RVSPLRPET,PPKTRVSPL,KTRVSPLRPE,EPPKT KIRC 7C S 388S]SPLRPETPKNGVSPLFPEPPKTRIS RVSPL N FAM4 c.1495A>G p.I499V ISSGNSFPPQQAGSPLKRPFSAAAA[p.I FSAAAAVAA,SAAAAVAAA,RPFSAAAAV,FSAAAAVAAA,S TGCT 8B1 499V]VAAAAAAAAAAAAAAAAAAPA AAAAVAAAA,RPFSAAAAVA PALAA FAM4 c.1546G>C p.A516 RPFSAAAAIAAAAAAAAAAAAAAAA[p. AAAPAPAPAL,APAPAPALAA TGCT 8B1 P A516P]PAPAPALAAAAAPALAAAAAP ALAAA FAM5 c.950A>G p.H317 SDATVEKDESHAGKVVLRSWYEKNK[p. KNKRIFPAS,KRIFPASRW,SWYEKNKRIF,KNKRIFPASR,YEK CLL 0A R H317R]RIFPASRWEPYDPEKKWDKYTI NKRIFPA,NKRIFPASRW R* FAM5 c.208G>A p.A70T LGMQSIPIATACTIYPKFFCETILD[p.A70 ILDTFDPYL,TILDTFDPY,DTFDPYLIA,ETILDTFDPY,TILDTFD BRCA 8BP T]TFDPYLIAMSSIYLAGKVEEQPLWAH PYL,ILDTFDPYLI,FFCETILDTF,DTFDPYLIAM FAM5 c.1204C>T p.R402 AGLKVLFKKTHRILRRLFNLCKRCH[p.R4 CQPRFRLPK,RCHCQPRFR,KRCHCQPRF,RCHCQPRFRL,HC CRC B C 02C]CQPRFRLPKERSLSYWWNRIQSLL QPRFRLPK,CKRCFICQPRF YC FAM5 c.1274C>G p.S425 WLTRIQSFLYCNENGLLGSFSEETH[p.S GSFSEETHW TGCT C W 425W]WCTCPNDQVVCTAFLPCTVGD ASACL FAM5 c.1369C>G p.R457 QVVCTAFLPCTVGDASACLTCAPDN[p. GTRCGTCNT,GTRCGTCNTG,LTCAPDNGTR LUAD C G R457G]GTRCGTCNTGYMLSQGLCKPE VAEST FAM7 c.56C>T p.S19L MQPPVPGPLGLLDPAEGL[p.S19L]LRR LLDPAEGLL,LLRRKKTSL,GLLDPAEGLL,GLLRRKKTSL,LLRR STAD 0B KKTSLWFVGSLLLVSVLIVTVGL KKTSLW,LRRKKTSLWF FAM7 c.829C>A p.P277 GFRLTPEPVPTCSSYPLPLQPCSRF[p.P2 LQPCSRFTV,FTVAPSSAL,TVAPSSALA,CSRFTVAPS,RFTVA LUAD 0B T 77T]TVAPSSALASSEDLQPPSPSSSGSG PSSA,QPCSRFTVA,FTVAPSSALA,CSRFTVAPSS,LQPCSRFT L VA,SRFTVAPSSA,RFTVAPSSAL FAM7 c.1333C>G p.H445 PSAEVWNENKERREKKDRHPSRKSS[p. PSRKSSDHRK CESC 1B D H445D]DHRKAGESHRRRAGDKNQKA SSHRSA FAM7 c.1747C>A p.L583 VDIVAKMVEKQNIEAKVEKAQGGQE[p. EKAQGGQEM,AQGGQEMEM,QEMEMISGT,EMEMISGT LUAD 1B M L583M]MEMISGTMTSEKTEMIVFETK M,MEMISGTMT,QEMEMISGTM,VEKAQGGQEM,KAQG SI* GQEMEM,MEMISGTMTS FAM7 c.68G>T p.G23V MSDCCSAPGISWEAGVGRPAVP[p.G2 RPAVPVLEL,VGRPAVPVL CESC 3A 3V]VLELQIRRGAMSEETVSESQFSLKTA FAM7 c.161C>T p.P54L FLTLVFALGFFFLLLPYLSYFHCDD[p.P54 LSYFHCDDL,YLSYFHCDDL LUAD 5A6 L]LPSPSPGKRKCPVGRRRRPRGRMKN H FAM7 c.910C>A p.R304 ASSRWQETARTSCAFNSSVQQDPLS[p. VQQDPLSSH,SSHPPETCQM LUAD 5A6 S R304S]SHPPETCQMEAGSLFLLSSDGQ NVVG FAM7 c.3793C>A p.R126 NSQGISSGDMGTSQVVHVHLEDSGI[p. HLEDSGISV,SVAQKQEPR,LEDSGISVA,HLEDSGISVA,SVA LUAD 5D1 5S R1265S]SVAQKQEPRVPTCVLQKCQVT QKQEPRV NFPPA FAM7 c.665T>C p.L222 PPQPVSPLDSKFPIDHSLPQQLPSP[p.L2 PQQLPSPPF,LPSPPFPPH,LPQQLPSPPF,QQLPSPPFPP THCA 5D5 P 22P]PFPPHHIQRAEPSLQPEASLSLNTV F FAM7 c.575G>T p.W19 TWAVPVSESNVAKLTNIYRDQSFTT[p. LLVATNTST,YRDQSFTTL,RDQSFTTLL,QSFTTLLVA,IYRDQ KIRC 8A 2L W192L]LLVATNTSTNDMIILQTLHWR SFTTL,YRDQSFTTLL,DQSFTTLLVA MQLSI FAM8 c.617G>A p.R206 DESNFNHFLNMTEKQGCSVQRLRNI[p. VQRLRNIQV,RLRNIQVRT,RNIQVRTVK,RLRNIQVRTV,VQ UCEC 3B Q R206Q]QVRTVKGQDYLSKTGAKFHGK RLRNIQVR,QVRTVKGQDY MEQKF FAM8 c.421G>A p.A141 SGGSVTLSESTAIISYGTTGLVTWD[p.A LVTWDTALY,GLVTWDTAL,VTWDTALYL,VTWDTALYLA,G TGCT 6A T 141T]TALYLAEWAIENPAVFTNRTVLEL LVTWDTALY,LVTWDTALYL,DTALYLAEWA,TALYLAEWAI GS FAM8 c.359G>A p.C120 RASCSPLSYAGLGSDGKWNLVMTRN[p. MTRNYFPTK,NYFPTKSTW,YFPTKSTWR,NLVMTRNYF,W TGCT 6C2P Y C120Y]YFPTKSTWRWQC* NLVMTRNY,VMTRNYFPTK,YFPTKSTWRW,MTRNYFPTKS, KWNLVMTRNY,NYFPTKSTWR,LVMTRNYFPT,WNLVMT RNYF,RNYFPTKSTW FARP1 c.1148C>T p.S383 KVQFERKHSKIHSIRSLASQPTELN[p.S3 QPTELNLEV,SQPTELNLEV,LASQPTELNL,QPTELNLEVL UCEC L 83L]LEVLEQSQQSTSLTFGEGAESPGG QS FARP1 c.896G>T p.R299 KRFLIKLRPDANSAYQDTLEFLMAS[p.R FLMASLDFC,TLEFLMASL,LMASLDFCK,EFLMASLDF,ASLD LUAD L 299L]LDFCKSFWKICVEHHAFFRLFEEP FCKSF,FLMASLDFCK,SLDFCKSFWK,DTLEFLMASL,MASLD KP FCKSF,LEFLMASLDF,ASLDFCKSFW,LDFCKSFWKI FAS c.781G>A p.E261 IAGVMTLSQVKGFVRKNGVNEAKID[p. GVNEAKIDK CESC K E261K]KIKNDNVQDTAEQKVQLLRNW HQLHG FASTK c.9_10insA p.K3fs MKK[p.K3fs]NTCFPRVIGYKYASSKSYL YLSILLESV,IGYKYASSK,KYASSKSYL,SYLSILLES,CFPRVIGYK, STAD D1 SILLESVSISTHQL* ASSKSYLSI,SSKSYLSIL,YKYASSKSY,SVSISTHQL,TCFPRVIG Y,FPRVIGYKY,KKNTCFPRV,SKSYLSILL,LESVSISTFI,ILLESVS IST,VIGYKYASSK,TCFPRVIGYK,CFPRVIGYKY,SYLSILLESV, SSKSYLSILL,NTCFPRVIGY,GYKYASSKSY,ESVSISTHQL,FPR VIGYKYA,YASSKSYLSI,MKKNTCFPRV,KKNTCFPRVI,YKYA SSKSYL,ASSKSYLSIL,LSILLESVSI FASTK c.1873C>G p.Q625 RFCSNSKHLLGKEAIKQRHLQLLGY[p.Q HLQLLGYEV,LQLLGYEVV,LLGYEVVQI,GYEVVQIPY,YEW BLCA D3 E 625E]EVVQIPYHEIGMLKSRRELVEYLQ QIPYH,HLQLLGYEVV,QLLGYEVVQI,LGYEVVQIPY,EVVQIP RK YHEI,RHLQLLGYEV FAT1 c.13076G>T p.R435 TKVVDLDPCLSKKPLEEKPSQPYSA[p.R SALESLSEV,KPSQPYSAL,QPYSALESL,YSALESLSEV,SQPYS LUAD 9L 4359L]LESLSEVQSLSSFQSESCDDNGY ALESL,LESLSEVQSL HWD FAT3 c.10720C>A p.H357 PTAIPLEIFIVTMEDDFPGGVIGKI[p.H3 KINATDQDM,KINATDQDMY,NATDQDMYDV,GKINATDQ LUAD 4N 574N]NATDQDMYDVLTFALKSEQKSL DM FKVN FAT3 c.12475G> p.A415 GLRPVVVPNIQAGHSYVGKEELIGI[p.A ELIGITVVL,ITVVLFVIF,TVVLFVIFI,KEELIGITV,LIGITVVLF,E UCEC A 9T 4159T]TVVLFVIFILVVLFIVFRKKVFRKN ELIGITVV,LIGITVVLFV,IGITVVLFVI,ITVVLFVIFI,TVVLFVIFI Y L,ELIGITVVLF,KEELIGITVV,GITVVLFVIF,EELIGITVVL FAT3 c.3797G>A p.R126 VVQVLDENDNKPQFPEKVYQIKLPE[p. KVYQIKLPEH,QIKLPEHDRK LUAD 6H R1266H]HDRKKRGEPIYRAFAFDRDEG PNAEI FAT3 c.5696G>T p.G189 TDVNDNPPVFTQAVFETILLLPTYV[p.G ILLLPTYVV,LLLPTYVVV,YVVVEVLKV,LPTYVVVEV,TILLLPT LUAD 9V 1899V]VVEVLKVSATDPDSEVPPELTYS YVV,ILLLPTYVVV,LLPTYVVVEV,PTYVVVEVLK,TYVVVEVL LME KV,LPTYVVVEVL FBRSL c.2507C>T p.A836 GRSGAPAEREAEPRVKESRSPAKEE[p.A EVAKMPARA,KEEVAKMPA,RSPAKEEVAK,SPAKEEVAKM, ACC 1 V 836V]VAKMPARASPPHSKAAPGDVKV EEVAKMPARA KEER FBXL1 c.306T>A p.S102 RIQQIIYCHKLTIILTKWRNTARHK[p.S1 RNTARHKRK,TARHKRKKK,KWRNTARHKR,RNTARHKRKK, CLL 3 R 02R]RKKKEDELILKHELQLKKWKNRLIL RKKKEDELIL K FBXL1 c.143T>G p.V48G RDKGRAAQVCTAWRDAAYHKSVWRG SVWRGGEAK,KSVWRGGEA,KSVWRGGEAK,GEAKLHLRR TGCT 4 [p.V48G]GEAKLHLRRANPSLFPSLQAR A GIRRV FBXO c.432G>T p.M14 KQPCTNDMAKSNSVGQDSCQDSEGD[p. CQDSEGDII,SEGDIIFPA,IIFPAESSCA,CQDSEGDIIF LUAD 18 4I M144I]IIFPAESSCALPQEGSAGPGSP GSAP FBXO c.432de|T p.F144f KRFFSEHVPCNGFSDIENLEGPEIF[p.F1 IFLRMNWCV,FLRMNWCVS,PEIFLRMNW,EIFLRMNWCV, STAD 21 s 44fs]LRMNWCVS* LEGPEIFLRM,GPEIFLRMNW FBXO c.1657A>G p.M55 HLPASRWGTPEPSLGARAPQDPGG[p. GVAQACEEY,APQDPGGVA,GGVAQACEEY HNSC 24 3V M553V]VAQACEEYLSQIHSCQTLQDR TEKMK FBXO c.1329_1330 p.G443 TPGEDGGEPGDAVAAAEQPAQCGQG[p. AQCGQGAAV,AVRAARGRE,QGAAVRAAR,GQGAAVRAA, LUAD 31 insG fs G443fs]AAVRAARGRELQE* VRAARGREL,AVRAARGREL,QPAQCGQGAA FBXW c.1268G>T p.G423 SDDNTLKVWSAVTGKCLRTLVGHTG[p. TLVGHTGVV,GVVWSSQMR,RTLVGHTGV,LVGHTGVVW, UCEC 7 V G423V]VVWSSQMRDNIIISGSTDRTLK TGVVWSSQM,RTLVGHTGVV,TLVGHTGVVW,HTGVVWS VWNA SQM FBXW c.1393C>T p.R465 DRTLKVWNAETGECIHTLYGHTSTV[p.R465C] STVCCMHLH,GHTSTVCCM,TLYGHTSTVC,TVCCMHLHEK, CESC,CRC, 7 C CCMHLHEKRVVSGSRDATLRVWDIET HTSTVCCMHL,YGHTSTVCCM STAD,UCEC, UCS FBXW c.1394G>A p.R465 DRTLKVWNAETGECIHTLYGHTSTV[p. STVHCMHLH,HCMHLHEKR,GHTSTVHCM,TVHCMHLHEK, CLL,CRC, 7 H R465H]HCMHLHEKRVVSGSRDATLRV HTSTVHCMHL,LYGHTSTVH,YGHTSTVHCM UCEC,UCS WDIET FBXW c.1436G>A p.R479 IHTLYGHTSTVRCMHLHEKRVVSGS[p. SQDATLRVW STAD,UCS 7 Q R479Q]QDATLRVWDIETGQCLHVLM GHVAAV FBXW c.1513C>G p.R505 DATLRVWDIETGQCLHVLMGHVAAV[p. VAAVGCVQY,HVAAVGCVQY BLCA,CESC, 7 G R505G]GCVQYDGRRVVSGAYDFMV HNSC,LUSC, KVWDPET UCS FBXW c.1513C>T p.R505 DATLRVWDIETGQCLHVLMGHVAAV[p. VAAVCCVQY,VLMGHVAAVC,HVAAVCCVQY,AVCCVQYD CRC,UCEC 7 C R505C]CCVQYDGRRVVSGAYDFMV GR KVWDPET FBXW c.1637C>T p.S546 FMVKVWDPETETCLHTLQGHTNRVY[p. LLQFDGIHV,VYLLQFDGI,TNRVYLLQF,YLLQFDGIH,YLLQF BLCA 7 L S546L]LLQFDGIHVVSGSLDTSIRVWD DGIHV,LLQFDGIHVV,RVYLLQFDGI,HTNRVYLLQF,LQGHT VETG NRVYL FBXW c.1745C>T p.S582 GSLDTSIRVWDVETGNCIHTLTGHQ[p. QLLTSGMEL,LLTSGMELK,HTLTGHQLL,IHTLTGHQL,GHQ CRC 7 L S582L]LLTSGMELKDNILVSGNADSTVK LLTSGM,QLLTSGMELK,IHTLTGHQLL,TGHQLLTSGM,HQL IWD LTSGMEL FBXW c.2065C>T p.R689 ESGGSGGVVWRIRASNTKLVCAVGS[p. KLVCAVGSW,GSWNGTEETK,TKLVCAVGSW CRC,UCEC, 7 W R689W]WNGTEETKLLVLDFDVDMK* UCS FBXW c.41G>A p.R14Q MNQELLSVGSKRR[p.R14Q]QTGGSLR KRRQTGGSL,RQTGGSLRG,KRRQTGGSLR,SKRRQTGGSL CRC 7 GNPSSSQVDEEQMNRVVEE FBXW c.893_894 p.G298 YDKKVTIYDPRDRMETRDALMGWGG[p. GWGGAFEGL,ALMGWGGAF,DALMGWGGAF,MGWGG STAD 9 insG fs p.G298fs]AFEGL* AFEGL FCAR c.697G>A p.V233 SNALELVVTDSIHQDYTTQNLIRMA[p.V RMAMAGLVL,MAMAGLVLV,AMAGLVLVA,LIRMAMAGL, HNSC M 233M]MAGLVLVALLAILVENWHSHTA TQNLIRMAM,IRMAMAGLV,MAGLVLVAL,NLIRMAMAGL, LNKE RMAMAGLVLV,MAMAGLVLVA,AMAGLVLVAL,LIRMAM AGLV,IRMAMAGLVL FCGB c.12055G> p.V401 VYYEPEQTVLIDNCRQQCTCHVGKV[p. VMVCQEHSCK UCS P A 9M V4019M]MVCQEHSCKPGQVCQPSGG ILSCVTK FCGB c.3064G>T p.A102 EALCGLCGNFNGDPADDLALRGGGQ[p. ALRGGGQSA,GQSANALAF,LALRGGGQSA,GGQSANALAF LUAD P 2S A1022S]SANALAFGNSWQEETRPGCG ATEPGD FCGB c.7478C>T p.A249 RFDFMGTCVYVLAQTCGTRPGLHRF[p. RPGLHRFVV,VVLQENVAW,GTRPGLHRFV,RPGLHRFVVL, PAAD P 3V A2493V]VVLQENVAWGNGRVSVTRVI FVVLQENVAW TVQVAN FCGR2 c.665T>G p.V222 SSKPVTITVQVPSMGSSSPMGIIVA[p.V IVAGVIATA,PMGIIVAGV,SPMGIIVAG,IIVAGVIATA,IVAG KIRP A G 222G]GVIATAVAAIVAAVVALIYCRKKR VIATAV,GVIATAVAAI,SPMGIIVAGV IS FCGRT c.118C>G p.P40A LFLLPGSLGAESHLSLLYHLTAVSS[p.P40 HLTAVSSAA,SSAAPGTPA,SAAPGTPAF,YHLTAVSSA,SSAA THCA A]AAPGTPAFWVSGWLGPQQYLSYNSL PGTPAF,YHLTAVSSAA,SAAPGTPAFW R FCRL2 c.1513G>T p.V505 MQQPESSANIRTLLENKDSQVIYSS[p.V SQVIYSSLK,QVIYSSLKK,SQVIYSSLKK,DSQVIYSSLK,KDSQV LUAD L 505L]LKKS* IYSSL FEM1 c.1858C>A p.L620 AIMNALIEAGAHMDATNAFKKTAYE[p. TAYEMLDEK,AFKKTAYEM,FKKTAYEML,YEMLDEKLL,KTA PRAD A M L620M]MLDEKLLARGTMQPFNYVTLQ YEMLDEK,EMLDEKLLAR,NAFKKTAYEM,YEMLDEKLLA CLAAR FER c.1422de|A p.L474f SEKPLAEQDWYHGAIPRIEAQELLK[p.L CIDSRALGF,RVMGNLVNM,ILMDRGDIL,LVNMSFLYI,NM STAD s 474fs]NKETFWCERVMGNLVNMSFLYI SFLYILM,LITCIDSRA,SYNMLITCI,RALGFQTFL,NLVNMSFL LMDRGDILSYNMLITCIDSRALGFQTFL Y,MDRGDILSY,SFLYILMDR,MLITCIDSR,ETFWCERVM,DIL NL* SYNMLI,MGNLVNMSF,CERVMGNLV,VNMSFLYIL,RGDIL SYNM,SRALGFQTF,LGFQTFLNL,KETFWCERV,GDILSYNM L,LMDRGDILSY,NLVNMSFLYI,MLITCIDSRA,ALGFQTFLNL, MSFLYILMDR,VMGNLVNMSF,LYILMDRGDI,KNKETFWC ER,GNLVNMSFLY,NMLITCIDSR,DSRALGFQTF,QELLKNKE TF,KETFWCERVM,LVNMSFLYIL,VNMSFLYILM,LSYNMLIT CI,TCIDSRALGF,SRALGFQTFL,GDILSYNMLI FERD3 c.275C>A p.P92H CEVDQGDGEEEEEEERGRGVSLLGR[p. SLLGRHKRK,GVSLLGRHK,VSLLGRHKR,HKRKRVITY,VSLLG LUAD L P92H]HKRKRVITYAQRQAANIRERKR RFIKRK,RGVSLLGRHK,SLLGRHKRKR,LGRHKRKRVI,RHKRK MFNL RVITY FEZ2 c.149C>T p.P50L NCNASPEPGAEAGAEAGGGADGFPA[p. ALACSLEEK,GGADGFPAL,ALACSLEEKL,FPALACSLEE ACC P50L]LACSLEEKLSLCFRPSDPGAEPP RTA FEZF2 c.244G>A p.E82K GSQGKKLLNLCSPLPCMIPLQPLGY[p.E YKVPSKTLL,MIPLQPLGYK,KVPSKTLLSY,LGYKVPSKTL,IPL CESC 82K]KVPSKTLLSYSELWKSSLRAGGGG QPLGYKV GG FGB c.1015G>C p.E339 NYCGLPGEYWLGNDKISQLTRMGPT[p. RMGPTQLLI,LTRMGPTQL,GPTQLLIEM,TRMGPTQLL,QLT LUAD Q E339Q]QLLIEMEDWKGDKVKAHYGG RMGPTQL,LTRMGPTQLL,SQLTRMGPTQ FTVQNE FGF14 c.686C>T p.T229 KPLEVAMYREPSLHDVGETVPKPGV[p. VMPSKSTSA,MPSKSTSAS,GVMPSKSTSA,VPKPGVMPSK, GBM M T229M]MPSKSTSASAIMNGGKPVNKS MPSKSTSASA,GETVPKPGVM KTT* FGF14 c.707C>T p.A236 YREPSLHDVGETVPKPGVTPSKSTS[p.A VTPSKSTSV,VSAIMNGGK,KSTSVSAIM,SKSTSVSAI,GVTPS CRC V 236V]VSAIMNGGKPVNKSKTT* KSTSV,SVSAIMNGGK,TPSKSTSVSA,SKSTSVSAIM FGFR3 c.1138G>A p.G380R VVLPAEEELVEADEAGSVYAGILSY[p.G YAGILSYRV,ILSYRVGFF,SYRVGFFLF,VYAGILSYR,GILSYRV BLCA 380R]RVGFFLFILVVAAVTLCRLRSPPKK GF,LSYRVGFFL,ILSYRVGFFL,RVGFFLFILV,SVYAGILSYR,VY G AGILSYRV,LSYRVGFFLF,SYRVGFFLFI,AGILSYRVGF,GILSY RVGFF,YRVGFFLFIL FGFR3 c.1711_1712 p.R571fs QGGPLYVLVEYAAKGNLREFLRARR[p. LLLRHLQAA,RARRAPGPG,LLRHLQAAR,RLRAGPGRA,GP KIRC insG R571fs]APGPGLLLRHLQAARGAAHLQ GHGVLGL,FLRARRAPG,LQAARGAAFI,REFLRARRA,ARRA GPGVLCLPGGPGHGVLGLPEVHPQGP PGPGL,RRAPGPGLL,RAPGPGLLL,RHLQAARGA,AHLQGP GCPQCAGDRGQRDEDRRLRAGPGRA GVL,LQGPGVLCL,LQEDDQRPA,LPGGPGHGV,CLPGGPGH QPRLLQEDDQRPAAREVDGA* GV,GLLLRHLQAA,LQAARGAAHL,LLQEDDQRPA,RARRAP GPGL,RLRAGPGRAQ,RAGPGRAQPR,LLLRHLQAAR,LPGG PGHGVL,RPAAREVDGA,FLRARRAPGP,REFLRARRAP,RRA PGPGLLL,RHLQAARGAA,HLQAARGAAH,AAHLQGPGVL, HLQGPGVLCL,LQEDDQRPAA FGFR3 c.2147C>A p.P716 GGSPYPGIPVEELFKLLKEGHRMDK[p.P HANCTHDLY,KHANCTHDLY,RMDKHANCTH,HANCTHDL KIRC H 716H]HANCTHDLYMIMRECWHAAPS YM QRPTF FGFR3 c.2420G>C p.*807 SSGDDSVFAHDLLPPAPPSSGGSRT[p.* RILPPGAEV,RLSADGETA,CVCVCAHPR,GSRTSRATG,GSLA MM S 807S]SRATGPQQCEGSLAAHPAAGAQ AHPAA,CVRILPPGA,LLTGAAAPR,LAAHPAAGA,ETATQSF PLPGMRLSADGETATQSFGLCVCVCVC GL,QSFGLCVCV,EVPWVSPLL,GPQQCEGSL,HPAAGAQPL, VCVCAHPRVPVCVRILPPGAEVPVVVSP SPLLCNGLL,QQCEGSLAA,AGAQPLPGM,AQPLPGMRL,AE LLCNGLLTGAAAPRGLCSGGTQCRM* VPWVSPL,LPPGAEVPW,VPWVSPLLC,SLAAHPAAGA,TQS FGLCVCV,GLCVCVCVCV,LLCNGLLTGA,WVSPLLCNGL,ILP PGAEVPW,ETATQSFGLC,CVCAHPRVPV,QPLPGMRLSA,H PRVPVCVRI,QQCEGSLAAH,ADGETATQSF,GETATQSFGL, AEVPWVSPLL,CEGSLAAFIPA,LPPGAEVPWV FGFR3 c.742C>T p.R248 RGNYTCVVENKFGSIRQTYTLDVLE[p.R DVLECSPHR,LECSPHRPI,LECSPHRPIL BLCA C 248C]CSPHRPILQAGLPANQTAVLGSD VEF FGFR3 c.746C>G p.S249 GNYTCVVENKFGSIRQTYTLDVLER[p.S DVLERCPHR,LERCPHRPI,CPHRPILQA,LERCPHRPIL BLCA,LUSC C 249C]CPHRPILQAGLPANQTAVLGSDV EFH FGFRL c.1435_1436 p.H479 LGPGPVAGPKLYPKLYTDIHTHTHT[p.H SVLDGTVSA,VLDGTVSAV,HTHTHTLSH,HTLSHTLTR,HTH BLCA 1 de|CA fs 479fs]LSHTLTRGGQGPPAHPLSVLDGT TLSHTL,RSCRRRQGT,DIHTHTHTL,GPPAHPLSV,PPAHPLS VSAVGTGGPARQADWEDGGRSCRRR VL,WPAPQAVCV,GQGPPAHPL,EEWPAPQAV,EEEWPAP QGTHGEEEWPAPQAVCV* QA,SVLDGTVSAV,HTHTHTLSHT,HTHTLSHTLT,LTRGGQG PPA,RSCRRRQGTH,GPPAHPLSVL,HPLSVLDGTV,TDIHTH THTL,IHTHTHTLSH,RQGTHGEEEW,EEWPAPQAVC,EEEW PAPQAV,GEEEWPAPQA FGFRL c.728G>T p.R243 KYTCRVSNRAGAINATYKVDVIQRT[p.R RTLSKPVLT,IQRTLSKPV,VIQRTLSKPV,TLSKPVLTGT,RTLS LUAD 1 L 243L]LSKPVLTGTHPVNTTVDFGGTTSF KPVLTG,IQRTLSKPVL,YKVDVIQRTL QC FGFRL c.820G>T p.V274 TGTHPVNTTVDFGGTTSFQCKVRSD[p. KVRSDLKPV,QCKVRSDLK,FQCKVRSDL,KVRSDLKPVI,DLK LUAD 1 L V274L]LKPVIQWLKRVEYGAEGRHNST PVIQWLK,CKVRSDLKPV IDVG FGGY c.412_413i p.G138 LDHRAVSQVNRINETKHSVLQYVGG[p. SVAERELER,LQYVGGGDV,AERELERDL,VLQYVGGGDV,LQ STAD nsG fs G138fs]GDVCGNAGPETSVAERELERD YVGGGDVC,AERELERDLL LLG* FHDC c.298de|T p.F100f PGLPPTTHMNGYSHLGKKKRMRSFF[p. RMRSFFGKL,RSFFGKLFR,KRMRSFFGK,SFFGKLFRR,KTPP STAD 1 s F100fs]GKLFRRSKFEAKPTSGPWQPG SLPFL,KKRMRSFFG,FGKLFRRSK,LFRRSKFEA,RSKFEAKPT, RNITTKLIQRPLRSSLGSRKTPPSLPFLGE TTKLIQRPL,IQRPLRSSL,PLRSSLGSR,GSRKTPPSL,TSGPWQ EEL* PGR,NITTKLIQR,GPWQPGRNI,LPFLGEEEL,MRSFFGKLF, GKLFRRSKF,RKTPPSLPF,KLFRRSKFEA,SLPFLGEEEL,RSFF GKLFRR,RMRSFFGKLF,KKRMRSFFGK,LFRRSKFEAK,RSKF EAKPTS,TTKLIQRPLR,IQRPLRSSLG,PLRSSLGSRK,GPWQP GRNIT,LIQRPLRSSL,KRMRSFFGKL,FGKLFRRSKF,SKFEAKP TSG,FEAKPTSGPW,SRKTPPSLPF,RKTPPSLPFL FHDC c.760C>T p.R254 SGDVSKLSLADSFLYGLIQVPNYSL[p.R2 YSLWIEAMV,SLWIEAMVL,LWIEAMVLK,WIEAMVLKK,IQ CRC 1 W 54W]WIEAMVLKKEFLPSCSSLYTDITVL VPNYSLW,NYSLWIEAM,IQVPNYSLWI,SLWIEAMVLK,NYS R LWIEAMV,YSLWIEAMVL,VPNYSLWIEA FHL1 c.552T>G p.D184 AKHCVKCNKAITSGGITYQDQPWHA[p. AECFVCVTC,QPWHAECFV,AECFVCVTCS CLL E D184E]ECFVCVTCSKKLAGQRFTAVED QYYC FIGNL c.926de|A p.K309f NGPKEDS5LPTFKTAKEQLWVDQQK[p. SVHQGLHMV,LSVHQGLHM,DQQKSTTNL,QKSTTNLSV,S STAD 1 s K309fs]STTNLSVHQGLHMVV* VHQGLHMVV,QQKSTTNLSV,TTNLSVHQGL,QKSTTNLSV H,NLSVHQGLHM FILIP1 c.1565T>A p.I522K LKDDLTKLKSFTVMLVDERKNMMEK[p. MMEKKKQEER CLL I522K]KKQEERKVDGLNKNFKVEQGK VMDVT FKBPL c.481G>C p.E161 GPPEGWTELTMGVGPWREETWGELI[p. ETWGELIQK,LIQKCLESM,ELIQKCLESM CESC Q E161Q]QKCLESMCQGEEAELQLPGH SGPPVR FKBPL c.959G>T p.R320 AQAALGNLEKATADLKKVLAIDPKN[p. VLAIDPKNL,KNLAAQEEL,VLAIDPKNLA LUAD L R320L]LAAQEELGKVVIQGKNQDAGLA QGLR FLG c.477de|A p.K159f KGNKGRSKSPRETGGKRHESSSEKK[p.K KTMIITQVKK,LIEKKNMEK,TIITQVKKR,QVKKRKTRL,KKKEKD STAD s 159fs]KEKDIHLLIEKKNMEKTIITQVKK IHL,KEKDIHLLI,KKNMEKTII,MEKTIITQV,KKRKTRLKI,NME RKTRLKILD* KTIITQV,LLIEKKNMEK,KTIITQVKKR,TIITQVKKRK,QVKKR KTRLK,ITQVKKRKTR,KKKEKDIHLL,TQVKKRKTRL,KKRKTR LKIL FLG c.8657G>A p.R288 ASTHADISRHSQAVQGQSEGSRRSR[p. GSRRSRHQG,RSRHQGSSV,RSRHQGSSVS,RRSRHQGSSV GBM 6H R2886H]HQGSSVSQDSDSEGHSEDSE RWSGSA FLG c.9761C>A p.P325 ERWSGSASRNHRGSVQEQSRHGSRH[p. GSRHHRSHH,QSRHGSRHHR LUAD 4H P3254H]HRSHHEDRAGHGHSADRS RQSGTRHA FLG2 c.1716G>T p.L572 GSGSSQSSGYGQYGSRETSGFGQHG[p. FGSGQSTGF,GFGSGQSTGF LUAD F L572F]FGSGQSTGFGQYGSGSGQSSGF GQHG FLG2 c.4634G>T p.G154 HTHGQSGSQHGESESIIHDRHRITH[p.G HVQTGDTTR LUAD 5V 1545V]VQTGDTTRHSYSGHEQTTQTG SRTTG FLG2 c.5703_570 p.H190 RRSGHSESSDSEVHSGGSHTHSGHT[p. HSSQETPNY,TWRVRIHSS,RVRIHSSQE,QVSTWRVRI,TQP GBM 4de|CA 1fs H1901fs]QPSQVSTWRVRIHSSQETPN SQVSTW,SQETPNYSW,HTHSGHTQPS,RVRIHSSQET,IHSS YSWTDRRYH* QETPNY,ETPNYSWTDR,HTQPSQVSTW,SQVSTWRVRI,SS QETPNYSW,QPSQVSTWRV FLI43 c.2549_255 p.L850f SHTFQLWRALGAGQPTSHLVLTTLL[p.L LVLTTLLGL,TLLGLSAGA,GLSAGATPA,ALCLGAEPA,AQPP PRAD 860 0insT s 850fs]GLSAGATPAHRCQRQQPLPQGE KLQHV,ATPAHRCQR,AARAAVCPG,GGGRAQPPK,EPAVH DLPAFAGCHEHAARAAVCPGVQAGRA HGAL,HRCQRQQPL,LSAGATPAH,PQGEDLPAF,HEHAARA GGLPQALPGPPHPDALCLGAEPAQRAP AV,VQAGRAGGL,RAGGLPQAL,AQRAPQAAG,LQHVTGGT QAAGPGGGRAQPPKLQHVTGGTEEPA E,LPQGEDLPA,HLVLTTLLGL,VLTTLLGLSA,AVCPGVQAGR, VHHGALA* AARAAVCPGV,AGRAGGLPQA,RAQPPKLQHV,LSAGATPA HR,FAGCHEHAAR,TTLLGLSAGA,HVTGGTEEPA,LPQGEDL PAF,LPGPPHPDAL,AHRCQRQQPL,GLSAGATPAH,GRAGG LPQAL,LQHVTGGTEE,EEPAVHHGAL,LPAFAGCHEH,LPQA LPGPPH,HEHAARAAVC,AEPAQRAPQA,TEEPAVHHGA FLNA c.3718G>A p.V124 GTHTITYIPLCPGAYTVTIKYGGQP[p.V1 TIKYGGQPM,YGGQPMPNF,KYGGQPMPNF,GQPMPNFP GBM 0M 240M]MPNFPSKLQVEPAVDTSGVQCY SK,QPMPNFPSKL,MPNFPSKLQV,VTIKYGGQPM GPGI FLNB c.1586_158 p.W52 LDGVYAFEYYPSTPGRYSIAITWGG[p. ITWGGTPHSK,YSIAITWGGT,IAITWGGTPH STAD 7insG 9fs W529fs]TPHSKEPL* FLNB c.1586de|G p.W52 FLDGVYAFEYYPSTPGRYSIAITWG[p.W VLGALGSMV,TTFQRAPLK,LALKRVCRK,TFQRAPLKF,FQR STAD 9fs 529fs]DTTFQRAPLKFKLALKRVCRKSVL APLKFK,RAPLKFKLA,PLKFKLALK,KFKLALKRV,KLALKRVCR, GALGSMVGLSGGQRTSW* RVCRKSVLG,TWGDTTFQR,MVGLSGGQR,DTTFQRAPL,A PLKFKLAL,AITWGDTTF,SVLGALGSM,KRVCRKSVL,LSGGQ RTSW,SVLGALGSMV,ALKRVCRKSV,KLALKRVCRK,ITWGD TTFQR,TFQRAPLKFK,IAITWGDTTF,TTFQRAPLKF,RVCRKS VLGA,DTTFQRAPLK,RAPLKFKLAL,LKRVCRKSVL,KSVLGAL GSM,FQRAPLKFKL,LKFKLALKRV,GLSGGQRTSW FLT3 c.1800_1801 p.600_ LQMVQVTGSSDNEYFYVDFREYEYD[p. YEYDFREYE,REYEYDFRE,REYEYDFREY,YEYDFREYEY,DFR LAML insTTCAG 601insF 600_601insFREYEYD]FREYEYDLKWEF EYEYDFR,VDFREYEYDF,YDFREYEYDL AGAATATG REYEYD PRENLEFGKVLGSGAFGKVMNATAYGI AATATGAT SKTGVSI FLT3 c.2503G>C p.D835 RDLAARNVLVTHGKVVKICDFGLAR[p. HIMSDSNYV,RHIMSDSNY,CDFGLARHI,HIMSDSNYVV,CD LAML H D835H]HIMSDSNYVVRGNARLPVKW FGLARHIM,ARHIMSDSNY,RHIMSDSNYV MAPESL FLT3 c.2503G>T p.D835 RDLAARNVLVTHGKVVKICDFGLAR[p. ICDFGLARY,YIMSDSNYV,RYIMSDSNY,CDFGLARYI,YIMS LAML Y D835Y]YIMSDSNYWRGNARLPVKW DSNYVV,KICDFGLARY,RYIMSDSNYV,CDFGLARYIM,ARYI MAPESL MSDSNY FLT3 c.2505T>A p.D835 RDLAARNVLVTHGKVVKICDFGLAR[p. EIMSDSNYV,REIMSDSNY,CDFGLAREI,EIMSDSNYVV,CDF LAML E D835E]EIMSDSNYVVRGNARLPVKW GLAREIM,AREIMSDSNY,REIMSDSNYV MAPESL FMN2 c.2252C>T p.S751 CLEALRLEEKEVRHHRILEAKSIQT[p.S7 FPTEEGGVL,LEAKSIQTF,QTFPTEEGGV,ILEAKSIQTF,FPTE BRCA F 51F]FPTEEGGVLTLPPVDGLPGRPPCPP EGGVLT G FMN2 c.2974C>A p.P992 GIPLPPPLPGAGIPPPPPLPGAGIP[p.P9 AGIPTPPPL LUAD T 92T]TPPPLPGAGIPPPPPLPGAGIPPPP P FMNL c.2779G>C p.E927 HFLDKAGSVSLDSVLADVRSLQRGL[p.E SLQRGLQLT,RSLQRGLQL,QLTQREFVR,LQRGLQLTQ,GLQ CESC 1 Q 927Q]QLTQREFVRQDDCMVLKEFLRA LTQREF,LQLTQREFV,GLQLTQREFV,RGLQLTQREF NSPT FMO3 c.1530C>A p.F510 AILTQWDRSLKPMQTRVVGRLQKPC[p. CLFFHWLKL,RLQKPCLFF,LFFHWLKLF,LQKPCLFFH,RLQKP CRC L F510L]LFFHWLKLFAIPILLIAVFLVLT* CLFFH,LQKPCLFFHW,CLFFHWLKLF,KPCLFFHWLK,GRLQ KPCLFF FMOD c.993C>A p.S331 QKIPPVNTNLENLYLQGNRINEFSI[p.S3 FSIRSFCTV,SIRSFCTVV,RSFCTVVDV,INEFSIRSF,FSIRSFCT KIRP R 31R]RSFCTVVDVVNFSKLQVLRLDGNE VV,RSFCTVVDVV,RINEFSIRSF,NEFSIRSFCT IK FN1 c.868C>T p.R290 RGEWKCERHTSVQTTSSGSGPFTDV[p. FTDVCAAVY,GPFTDVCAAV UCEC C R290C]CAAVYQPQPHPQPPPYGHCVT DSGVV FNBP4 c.172_177d p.TT58 PEPDTEPDSTAAVPSQPAPSAATTT[p.T APSAATTTA,ATTTAVTAAA,APSAATTTAV PRAD e|ACCACC de| T58de|]AVTAAAASDDSPSEDEQEAVQ EVPRVVQNPP FNDC c.1955G>A p.R652 QGTSHRPSLPASLNDNDLVDSDEDE[p. HAVGSLHPK,DEHAVGSLH,DEDEHAVGSL CRC 1 H R652H]HAVGSLHPKGAFAQPRPALSPS RQSP FNDC c.3535_353 p.D118 APGKSEPPSKRPLSSKSQQSVSAED[p.D AEDEEEDAGF PAAD 1 7de|GAC 0de| 1180de|]EEEDAGFFKGGKEDLLSSSVP KWPSSST FOLH1 c.1501de|A p.S501f NLTKELKSPDEGFEGKSLYESWTKK[p.S KVLPQSSVA,YESWTKKVL,KKVLPQSSV,SLYESWTKKV,LYE STAD s 501fs]VLPQSSVACPG* SWTKKVL,KKVLPQSSVA FOLH1 c.1927G>T p.A643 HPQEMKTYSVSFDSLFSAVKNFTEI[p.A KNFTEISSK,NFTEISSKF,EISSKFSER,ISSKFSERL,EISSKFSERL, LUAD S 643S]SSKFSERLQDFDKSNPIVLRMMN KNFTEISSKF DQL FOXD c.1215de|C p.C405f GQFCSNSSSIRRTAPTAALPPRARC[p.C RARCGRAPV,CGRAPVGLV,EVSGSGGGL,APVGLVGAA,RA KIRC 4L4 s 405fs]GRAPVGLVGAAEVSGSGGGL* RCGRAPVG,AEVSGSGGGL FOXK1 c.1060C>T p.R354 SGIYAHITKHYPYYRTADKGWQNSI[p.R WQNSIWHNL,NSIWHNLSL,WHNLSLNRY,SIWHNLSLNR, CRC W 354W]WHNLSLNRYFIKVPRSQEEPGK GWQNSIWHNL,IWHNLSLNRY,WHNLSLNRYF GSFW FOXN c.287de|C p.P96fs NLLKSFGESVLRSVSPVQDLDDDTP[p.P TMPGRTPTA,LTCPTMPGR,AASYLWPSR,SYLWPSRTL,DT CRC,STAD 3 96fs]HPLPTLTCPTMPGRTPTANPPTPS PHPLPTL,SAASYLWPS,LPTLTCPTM,PPTPSAASY,TPSAASY AASYLWPSRTLQPSACQ* LW,SAASYLWPSR,ASYLWPSRTL,TLTCPTMPGR,HPLPTLT CPT,CPTMPGRTPT,WPSRTLQPSA,NPPTPSAASY FOXQ c.404C>T p.S135 RSKPYTRRPKPPYSYIALIAMAIRD[p.S1 AIRDLAGGR,IAMAIRDLA,ALIAMAIRDL,LIAMAIRDLA,AIR BLCA 1 L 35L]LAGGRLTLAEINEYLMGKFPFFRGS DLAGGRL,MAIRDLAGGR,RDLAGGRLTL Y FOXRE c.407G>T p.R136 SVGGICQQFSLPENIQLSLFSASFL[p.R1 SLFSASFLL,FSASFLLNI,FLLNINEYL,LLNINEYLA,SFLLNINEY, LUAD D1 L 36L]LNINEYLAVVDAPPLDLRFNPSGYL LNINEYLAV,FLLNINEYLA,LLNINEYLAV,ASFLLNINEY,LFSA L SFLLNI,SFLLNINEYL,LSLFSASFLL,LNINEYLAVV FPGS c.64A>G p.I22V MSRARSHLRAALFLAAASARG[p.I22V] SARGVTTQV,GVTTQVAAR,VTTQVAARR,LAAASARGV,FL ACC VTTQVAARRGLSAWPVPQEPSMEYQD AAASARGV,ASARGVTTQV,SARGVTTQVA FPGT- c.1364G>A p.R455 NVININHQGRDGHTGLHSACYHGHI[p. CYHGHIHLV,HIHLVQFLL,ACYHGHIHL,HGHIHLVQF,GHIH CRC TNNI3 H R455H]HLVQFLLDNGADMNLVACDPS LVQFL,YHGHIHLVQF,HSACYHGFIIH,SACYHGHIHL,GHIHL K RSSGE VQFLL FPR2 c.161G>A p.R54Q PLVVLGVTFVLGVLGNGLVIWVAGF[p. FQMTRTVTT,QMTRTVTTI,WVAGFQMTR,VIWVAGFQM, GBM R54Q]QMTRTVTTICYLNLALADFSFTA AGFQMTRTV,FQMTRTVTTI,IWVAGFQMTR,LVIWVAGF TLP QM FRAS1 c.1145G>T p.C382 FMSSNASEVKRIPEGEKWEDGPCKV[p. WEDGPCKVF,FECRGAQVT,KVFECRGAQV,KWEDGPCKVF LUAD F C382F]FECRGAQVTCYEPSCPPCPVGT LALE FRG1 c.254_256d p.E86d AIEMDKGTYIHALDNGLFTLGAPHK[p.E FTLGAPHKV PRAD e|AAG e| 86de|]VDEGPSPPEQFTAVKLSDSRIALK SGYG FRG1 c.101T>C p.I34T RIALKSGYGKYLGINSDELVGHSDA[p.I3 DELVGHSDAT PRAD B 4T]TGPREQWEPVFQNGKMALLASNS CFI FRG1 c.110G>A p.R37K LKSGYGKYLGINSDELVGHSDAIGP[p.R GPKEQWEPV,DAIGPKEQW,VGHSDAIGPK UCS B 37K]KEQWEPVFQNGKMALLASNSCFI RCN FRG1 c.115C>A p.Q39K SGYGKYLGINSDELVGHSDAIGPRE[p.Q GPREKWEPV,DAIGPREKW,HSDAIGPREK,KWEPVFQNGK, CLL B 39K]KWEPVFQNGKMALLASNSCFIRC GPREKWEPVF NEA FRG1 c.125C>A p.P42Q GKYLGINSDELVGHSDAIGPREQWE[p. GPREQWEQV,EQVFQNGKM,GPREQWEQVF,WEQVFQN PRAD B P42Q]QVFQNGKMALLASNSCFIRCNE GKM,QVFQNGKMAL,REQWEQVFQN AGDI FRG1 c.145A>G p.M49 SDELVGHSDAIGPREQWEPVFQNGK[p. FQNGKVALL,FQNGKVALLA,VFQNGKVALL,VALLASNSCF, TGCT B V M49V]VALLASNSCFIRCNEAGDIEAKS WEPVFQNGKV KTA FRG1 c.148G>C p.A50P DELVGHSDAIGPREQWEPVFQNGKM[p. FQNGKMPLL,VFQNGKMPL,MPLLASNSC,PLLASNSCF,FQ KIRP,PRAD, B A50P]PLLASNSCFIRCNEAGDIEAKSK NGKMPLLA,VFQNGKMPLL,MPLLASNSCF SKCM TAG FRG1 c.155T>C p.L52S LVGHSDAIGPREQWEPVFQNGKMAL[p. SASNSCFIR,LSASNSCFI,ALSASNSCF,FQNGKMALSA,ALSA PRAD,UCS B L52S]SASNSCFIRCNEAGDIEAKSKTA SNSCFI,KMALSASNSC,LSASNSCFIR,MALSASNSCF GEE FRG1 c.157G>A p.A53T VGHSDAIGPREQWEPVFQNGKMALL[p. LLTSNSCFI,LTSNSCFIR,ALLTSNSCF,ALLTSNSCFI,FQNGK GBM,PRAD B A53T]TSNSCFIRCNEAGDIEAKSKTA MALLT,KMALLTSNSC,LLTSNSCFIR,MALLTSNSCF GEEE FRG1 c.163A>G p.N55D HSDAIGPREQWEPVFQNGKMALLAS[p. LLASDSCFI,LASDSCFIR,ALLASDSCF,ALLASDSCFI,LLASDS PRAD B N55D]DSCFIRCNEAGDIEAKSKTAGEE CFIR,MALLASDSCF EMI FRG1 c.175A>G p.I59V IGPREQWEPVFQNGKMALLASNSCF[p. LLASNSCFV,LASNSCFVR,ALLASNSCFV,LLASNSCFVR PRAD,SKCM B I59V]VRCNEAGDIEAKSKTAGEEEMIK SLS FRG1 c.194G>A p.G65E WEPVFQNGKMALLASNSCFIRCNEA[p. FIRCNEAEDI UCS B G65E]EDIEAKSKTAGEEEMIKSLSHSLP SS FRG1 c.29T>C p.I10T MAVKLSDSR[p.I10T]TALKSGYGKYLGI LSDSRTALK,KLSDSRTAL,TALKSGYGK,RTALKSGYG,KLSDS PRAD,UCS B NSDELVGHSDAIG RTALK,RTALKSGYGK,AVKLSDSRTA,TALKSGYGKY,VKLSD SRTAL FRG1 c.31G>A p.A11T MAVKLSDSRI[p.A11T]TLKSGYGKYLGI KLSDSRITL,ITLKSGYGK,LSDSRITLK,TLKSGYGKY,SRITLKSG PRAD B NSDELVGHSDAIGP Y,TLKSGYGKYL,KLSDSRITLK,RITLKSGYGK,ITLKSGYGKY,V KLSDSRITL FRG1 c.39A>T p.K13N MAVKLSDSRIAL[p.K13N]NSGYGKYLG IALNSGYGK,SRIALNSGY,ALNSGYGKY,ALNSGYGKYL,RIAL GBM,PRAD, B INSDELVGHSDAIGPRE NSGYGK,IALNSGYGKY,DSRIALNSGY UCS FRG1 c.59T>C p.L20P MAVKLSDSRIALKSGYGKY[p.L20P]PGI YPGINSDEL,KYPGINSDEL,KSGYGKYPGI,YPGINSDELV KIRP B NSDELVGHSDAIGPREQWEPVFQ FRG1 c.95A>T p.D32V DSRIALKSGYGKYLGINSDELVGHS[p.D ELVGHSVAI,VAIGPREQW,DELVGHSVA,NSDELVGHSV,DE PRAD,UCS B 32V]VAIGPREQWEPVFQNGKMALLAS LVGHSVAI NSC FRG2 c.424G>T p.D142 ECSLSLNKKSRSSTPVHNSEIQETC[p.D1 NSEIQETCY,YAHHRGRSR,CYAHHRGR,SEIQETCYA,IQET LUAD B Y 42Y]YAHHRGRSRACTGRSKRHRSRALG CYAHH,ETCYAHHRGR,CYAHHRGRSR,YAHHRGRSRA,SEI VQ QETCYAH FRMD c.3014de|C p.P100 CKATSAALPQSQRSSTPSSEIGATP[p.P1 SEIGATPQA,SEIGATPQAA STAD 4A 5fs 005fs]QAAPTTS* FRMP c.3277G>C p.E109 APKYTEPLLSPRDEPRSDECGINPG[p.E NPGQKIAS,GQKIASIP,GQKIASIPTK LUAD D1 3Q 1093Q]QKIASIPTKEEPQGQLSLERDRE VTN FRS2 c.140T>C p.L47S KVINVDDDGNELGSGIMELTDTELI[p.L LTDTELISY,DTELISYTR,ELISYTRKR,ISYTRKRDSV,SYTRKRD TGCT 47S]SYTRKRDSVKWHYLCLRRYGYDSN SVK,ELTDTELISY LF FSHB c.128C>A p.T43N CNSCELTNITIAIEKEECRFCISIN[p.T NTWCAGYCY,INNTWCAGY,FCISINNTW,RFCISINNTW,SI LUAD 43N]NTWCAGYCYTRDLVYKDPARPKIQKT NNTWCAGY,NTWCAGYCYT FUBP1 c.1288C>T p.R430 QSGARIELQRNPPPNADPNMKLFTI[p. CGTPQQIDY,FTICGTPQQI UCEC C R430C]CGTPQQIDYARQLIEEKIGGPV NPLG FUT6 c.418_419i p.S140f NPSAQLPRSPRRQGQRWIWFSMESP[p. VLSGLRELL,FLQGLLETA,GLLETAGGI,NLIFLGPHL,HLSGGL KIRC nsA s S140fs]KPLLAAESHGRILQSHHVLPQ IYL,FSMESPKPL,VLPQRLRFIL,ALRLAGAVV,GLGSVQLGA,P RLRHLHALRLAGAVVRPACPPTAQPLG LPELLSLA,LLSLAGDAA,LLQLGTRFL,FLGPHLSGG,IWFSME QDRAGGLGSVQLGAKLRQGALLPEPA SPK,RLRHLHALR,ASLLQLGTR,LSGGLIYLR,AWAARNLIF,RI GPSQGGRVRTLPQAPAPGNFIDGDAVP LQSHHVL,VVRPACPPT,KLRQGALLP,RVRTLPQAP,GLRELL VQVLSGLRELLAPRLHHREAVEERPGGL APR,RARGAGPQQ,ATRRLHPRG,RLHPRGRLP,GTRFLQGL GRARGAGPQQKQLREVPATRRLHPRG L,AARNLIFLG,QSHHVLPQR,LLAPRLHHR,QLREVPATR,PA RLPEPQGPGPVPAGAGQGPRPLPELLS TRRLHPR,GWCGAWAAR,ESPKPLLAA,DAAASLLQL,WAA LAGDAAASLLQLGTRFLQGLLETAGGIQ RNLIFL,RPACPPTAQ,VPVQVLSGL,APRLHHREA,HPRGRLP VPDTRHSGLVHLRGWCGAWAARNLIF EP,GPRPLPELL,RPLPELLSL,VPDTRHSGL,GPHLSGGLI,QRL LGPHLSGGLIYLRTRLPEASPA* RHLHAL,GAKLRQGAL,SLLQLGTRF,HLRGWCGAW,SMESP KPLL,MESPKPLLA,LQSHHVLPQ,LRHLHALRL,RHLHALRLA, HLHALRLAG,AKLRQGALL,RQGALLPEP,SQGGRVRTL,KQL REVPAT,REVPATRRL,LSLAGDAAA,LAGDAAASL,LETAGGI QV,TRHSGLVHL,RGWCGAWAA,GAWAARNLI,FSMESPKP LL,LLAAESHGRI,RLAGAVVRPA,GLRELLAPRL,SLAGDAAAS L,SLLQLGTRFL,FLGPHLSGGL,RLRHLHALRL,HLHALRLAGA, VLSGLRELLA,LLSLAGDAAA,QLGTRFLQGL,LLETAGGIQV, HLRGWCGAWA,WIWFSMESPK,GLGSVQLGAK,HLSGGLI YLR,GAWAARNLIF,AWAARNLIFL,HGRILQSHHV,HVLPQR LRHL,ALRLAGAVVR,VVRPACPPTA,KLRQGALLPE,GGRVR TLPQA,RVRTLPQAPA,RTLPQAPAPG,RARGAGPQQK,ATR RLHPRGR,RLHPRGRLPE,RGWCGAWAAR,ELLAPRLHHR, QLREVPATRR,VPATRRLHPR,EAVEERPGGL,QVPDTRHSG L,LPQRLRHLHA,APGNHDGDAV,APRLHHREAV,GPQQKQ LREV,LPEPQGPGPV,PQRLRHLHQL,GPHLSGGLIY,MESPK PLLAA,LAAESHGRIL,GRILQSHHVL,HALRLAGAVV,RAGGL GSVQL,RQGALLPEPA,VQVLSGLREL,RELLAPRLHH,QQKQ LREVPA,REVPATRRLH,GQGPRPLPEL,GDAAASLLQL,ASLL QLGTRF,LQLGTRFLQG,RFLQGLLETA,IQVPDTRHSG,VHLR GWCGAW,RNLIFLGPFIL,AESHGRILQS,PELLSLAGDA,VPD TRHSGLV FYB c.972de|G p.G324 NQEELASGTPPARFPKAPSKLTVGG[p. LTVGGHGA,GGHGAKVR,HGAKVRKRK,KVRKRKRE,RI STAD fs G324fs]HGAKVRKRKRETRIQPPRNRS QPPRNRS,RNRSHCLPC,TVGGHGAKV,PPRNRSHCL,HQNP HCLPCLPWVHLHQNPTDHQMLT* TDHQM,IQPPRNRSH,SHCLPCLPW,LPCLPWVHL,LPWVH LHQN,CLPCLPWVHL,KLTVGGHGAK,KVRKRKRETR,RIQPP RNRSH,RNRSHCLPCL,ETRIQPPRNR,LTVGGHGAKV,QPPR NRSHCL,RSHCLPCLPW,LHQNPTDHQM,HQNPTDHQML, LPWVHLHQNP FZD3 c.1099G>A p.D367 LTIILLAMNKIEGDNISGVCFVGLY[p.D3 NVDALRYFV,GLYNVDALR,LYNVDALRY,YNVDALRYF,GVC CRC N 67N]NVDALRYFVLAPLCLYVVVGVSLLL FVGLYNV,GLYNVDALRY,LYNVDALRYF,YNVDALRYFV A FZD6 c.1247G>A p.R416 ISLNHVRQVIQHDGRNQEKLKKFMI[p. KLKKFMIQI,IQIGVFSG,KFMIQIGVF,QIGVFSGLY,KKFMI UCEC Q R416Q]QIGVFSGLYLVPLVTLLGCYVYE QIGV,FMIQIGVFSG,MIQIGVFSGL,KLKKFMIQIG,IQIGVFS QVN GLY,KKFMIQIGVF GABR c.218G>A p.R73H LSPKHAPDIPDDSTDNITIFTRILD[p.R73 ILDHLLDGY,IFTRILDHL,HLLDGYDNR,FTRILDHLL,HLLDGY UCEC A3 H]HLLDGYDNRLRPGLGDAVTEVKTDIY DNRL,TIFTRILDHL,IFTRILDHL,RILDHLLDGY GABR c.1379G>A p.R460 PFSRANAAETISAARALPSASPTSI[p.R460 SIQTGYMPR,IQTGYMPRK,SPTSIQTGY,SIQTGYMPRK,TSI CRC,UCEC A4 Q Q]QTGYMPRKASVGSASTRHVFGSR QTGYMPR,ASPTSIQTGY,SPTSIQTGYM,IQTGYMPRKA LQR GABR c.377G>A p.S126 RQSWKDERLRFKGPMQRLPLNNLLA[p. NKIWTPDTF,ANKIWTPDTF,NKIWTPDTFF CRC A5 N S126N]NKIWTPDTFFHNGKKSIAHNM TTPNK GABR c.670C>A p.Q224 SEVVYVWTNGSTKSVVVAEDGSRLN[p. KYHLMGQTV,GSRLNKYHL,SRLNKYHLM,GSRLNKYHLM,A LUAD A5 K Q224K]KYHLMGQTVGTENISTSTGEYT EDGSRLNKY,NKYHLMGQTV IMTA GABR c.940G>A p.V314I SARHSLPKVSYATAMDWFIAVCFAF[p. FIAVCFAFI,FAFIFSALI,FIFSALIEF,IAVCFAFIF,CFAFIFSAL, GBM A6 V314I]IFSALIEFAAVNYFTNLQTQKAKR FIFSALIEFA,WFIAVCFAFI,CFAFIFSALI,AFIFSALIEF, KA FIAVCFAFIF,VCFAFIFSAL GABR c.1246C>T p.R416 KATMYSYDSASIQYRKPLSSREAYG[p.R SSREAYGCA,EAYGCALDR,SREAYGCAL,SSREAYGCAL PRAD B1 C 416C]CALDRHGVPSKGRIRRRASQLKV KIP GABR c.1498G>A p.D500 RSLPHKKTHLRRRSSQLKIKIPDLT[p.D5 LTNVNAIDR,IKIPDLTNV,KIKIPDLTNV,KIPDLTNVNA,DLTN CRC B3 N 00N]NVNAIDRWSRIVFPFTFSLFNLVY VNAIDR,NVNAIDRWSR,IPDLTNVNAI WL GABR c.1236de|G p.Q412 GSYRSVGVETGETKKEGAARSGGQG[p. FLGERALGL,RLRPSMSST,ATLACPGAR,ALGLPSPLR,RVSK STAD D fs Q412fs]ASVPGSGPSTQTPLTFTPALCS WDDSR,TFTPALCSL,AARSGGQGA,RSGGQGASV,SLRRLR LRRLRPSMSSTGRHTPCEHRTQATLAC PSM,RQLPRNFLG,RALGLPSPL,KWDDSRPRK,KTRGSLGLP, PGARRQLPRNFLGERALGLPSPLRVSK FTPALCSLR,ALCSLRRLR,TLACPGARR,QTPLTFTPA,TPLTF WDDSRPRKTRGSLGLPEL* TPAL,RPRKTRGSL,PSTQTPLTF,CEHRTQATL,TQATLACPG, ARRQLPRNF,RRQLPRNFL,RNFLGERAL,GERALGLPS,RKTR GSLGL,RGSLGLPEL,ALGLPSPLRV,ATLACPGARR,RALGLPS PLR,CSLRRLRPSM,SLRRLRPSMS,RLRPSMSSTG,RTQATLA CPG,KTRGSLGLPE,TFTPALCSLR,QTPLTFTPAL,LTFTPALCS L,TPALCSLRRL,LPRNFLGERA,RPRKTRGSLG,GSGPSTQTPL, GPSTQTPLTF,TQTPLTFTPA,TQATLACPGA,LACPGARRQL, GARRQLPRNF,RQLPRNFLGE,ERALGLPSPL,TRGSLGLPEL, LPSPLRVSKW,CEHRTQATLA,GERALGLPSP GABR c.613G>A p.E205 LRLTINAECYLQLHNFPMDEHSCPL[p.E KFSSYGYPK,PLKFSSYGY,DEHSCPLKF,HSCPLKFSSY,CPLKF SKCM G1 K 205K]KFSSYGYPKNEIEYKWKKPSVEVA SSYGY,MDEHSCPLKF DP GABR c.1103C>T p.A368 VSYVKAVDIYLWVSFVFVFLSVLEY[p.A VFLSVLEYV,FLSVLEYVA,VAVNYLTTV,VLEYVAVNY,LEYVA PRAD R2 V 368V]VAVNYLTTVQERKERKLREKFPC VNYL,FVFLSVLEYV,FLSVLEYVAV,VLEYVAVNYL,YVAVNYL MCG TTV,SVLEYVAVNY,LEYVAVNYLT GADL c.1054C>A p.L352I VAWNPHKMLMAGIQCCALLVKDKSD[p. KSDILKKCY,ILKKCYSAK,ILKKCYSAKA,LVKDKSDILK,DILKKC LUAD 1 p.L352I]ILKKCYSAKASYLFQQDKFYDV YSAK SYDT GAL3S c.811G>T p.A271 ESLVLLRRLLAWDLDDVLYAKLNAR[p.A SASSRLAAI,KLNARSASS,RSASSRLAA,NARSASSRL,YAKLN LUAD T3 S 271S]SASSRLAAIPAALARAARTWNAL ARSA,VLYAKLNARS,KLNARSASSR,NARSASSRLA,RSASSR DAG LAAI,LNARSASSRL,ARSASSRLAA GALN c.1072G>T p.G358 LEIVTCSHVGHVFRKATPYTFPGGT[p.G GGTCHVINK,YTFPGGTCH,FPGGTCHVI,YTFPGGTCHV,TF LUSC T13 C 358C]CHVINKNNRRLAEVWMDEFKDF PGGTCHVI FYII GALN c.702T>A p.D234 VNRDWLQPLLHRVKEDYTRVVCPVI[p. RVVCPVIEI,IEIINLDTF,CPVIEIINL,EIINLDTFTY,RVVCPVIEII LUAD T14 E D234E]EIINLDTFTYIESASELRGGFDWS LH GALN c.950_951i p.W31 GIFVIDKSWFNHLGKYDAQMDIWGG[p. AQMDIWGGR,MDIWGGREF,DAQMDIWGGR,QMDIWG STAD TL1 nsG 7fs W317fs]REF* GREF GALN c.1183G>A p.E395 AMDRHYFQNTGAYDSLMSLRGGENL[p. SLRGGENLK,GGENLKLSF,NLKLSFKAW,LKLSFKAWL,SLRG UCEC TL2 K E395K]KLSFKAWLCGGSVEILPCSRV GENLKL,MSLRGGENLK,NLKLSFKAWL,RGGENLKLSF,GEN GHIYQ LKLSFKA GALN c.133G>A p.A45T TALLFIYLHHNHVSSWQKKSQEPLS[p.A LSTWSPGKK,KSQEPLSTW,KKSQEPLSTW LIHC TL5 45T]TWSPGKKVHQQIIYGSEQIPKPHVI V GALN c.785G>T p.R262I LEPLLHAIAKDPKMVVCPLIDVIDD[p.R VIDDITLEY,PLIDVIDDI,VIDDITLEYK,DVIDDITLEY,ITLEYKP CRC TL5 262I]ITLEYKPSPLVRGTFDWNLQFKW SPL,CPLIDVIDDI DNV GALN c.1694_169 p.K567 WGYRKDRTLFHPVSNSCMDCNPAEK[p. NPAEKIFMA,CMDCNPAEKI,NPAEKIFMAR,MDCNPAEKIF BRCA TL6 6de|AGA de| p.K567de|]IFMARCDPLSETQQWIFEHI NMTVLEKF GARS c.124C>G p.P42A LLLLPPRLLARPSLLLRRSLSAASC[p.P42 RSLSAASCA,LSAASCAPI,APISLPAAA,AASCAPISL,SLSAAS ACC A]APISLPAAASRSSMDGAGAEEVLAPL CAPI,SAASCAPISL GART c.2420de|A p.K807f IESMQINGSVLKNGSLTNHFSFEKK[p.K FEKKRPEWL,FSFEKKRPEW OV s 807fs]RPEWLS* GAS2L c.566A>C p.D189 AAPTLVQLEEEIEEEVRRELALPPP[p.D1 RELALPPPA,LPPPAPSPPA,RELALPPPAP TGCT 2 A 89A]APSPPAPPRRQPCHFRNLDQMV QSLV GAS6 c.449de|G p.G150 CDRKGTQACQDLMGNFFCLCKAGWG[p. TTSRVASTV,ATAASSSPL,KMSTNAARR,GWGAGSATK,AT STAD fs p.G150fs]AGSATKMSTNAARRTGAAS KMSTNAA,ARRTGAASR,RTGAASRSA,ASRSATTSR,RSATT RSATTSRVASTVPATAASSSPLMAGPAK SRVA,STVPATAAS,NAARRTGAA,WGAGSATKM,SRVAST T* VPA,TAASSSPLM,ATTSRVASTV,RVASTVPATA,ATKMSTN AAR,AASRSATTSR,SSPLMAGPAK,AGWGAGSATK,STNAA RRTGA,AARRTGAASR,RTGAASRSAT,ASRSATTSRV,TSRV ASTVPA,ATAASSSPLM,SRVASTVPAT GAS8 c.937C>A p.R313 EEMSEMQKQLANYERDKQILLCTKA[p. ILLCTKASL,LLCTKASLK,KASLKVREK,CTKASLKVR,SLKVREK LUAD S R313S]SLKVREKELKDLQWEHEVLEQR EL,LLCTKASLKV,ILLCTKASLK,SLKVREKELK,KQILLCTKAS FTKV GATA c.1002_100 p.N334 ARRAGTSCANCQTTTTTLWRRNANG[p. CLQCLWALL,WALLQASQY,RNANGGPCL,LWALLQASQY, BRCA 3 3insG fs N334fs]GPCLQCLWALLQASQY* RRNANGGPCL,LQCLWALLQA GATA c.1200_120 p.H400 CKKVHDSLEDFPKNSSFNPAALSRH[p.H VLPEPHLAL,ALQPLQPHA,AIQPVLWTT,MLTGPPARV,FLK BRCA 3 1insA fs 400fs]NVLPEPHLALQPLQPHADHAHA AESKIM,IMFATLQRS,YMFLKAESK,KIMFATLQR,SMLTGP DAPAIQPVLWTTPPLQHGHRHGLEPCS PAR,HFCRSSIMK,MFLKAESKI,CSMLTGPPA,RSSIMKPKR,I MLTGPPARVPAVPFDLHFCRSSIMKPK MKPKRDGY,KAESKIMFA,VPFDLHFCR,AALSRHNVL,EPHL RDGYMFLKAESKIMFATLQRSSLWCLC ALQPL,GPPARVPAV,KPKRDGYMF,FATLQRSSL,DLHFCRS SNH* SI,LHFCRSSIM,ESKIMFATL,LALQPLQPH,LQPHADHAH,H AHADAPAI,LQHGHRHGL,RHGLEPCSM,PARVPAVPF,PAV PFDLHF,LKAESKIMF,ATLQRSSLW,LQRSSLWCL,AESKIMF AT,ADAPAIQPV,APAIQPVLW,SMLTGPPARV,YMFLKAES KI,LQRSSLWCL,CSMLTGPPAR,LHFCRSSIMK,FCRSSIMK PK,IMKPKRDGYM,GYMFLKAESK,SIMKPKRDGY,TTPPLQ HGHR,AVPFDLHFCR,HADAPAIQPV,NPAALSRHNV,QPVL WTTPPL,KPKRDGYMFL,DLHFCRSSIM,MFATLQRSSL,FLK AESKIMF,RHNVLPEPHL,HLALQPLQPH,ADAPAIQPVL,HR HGLEPCSM,ARVPAVPFDL,VPAVPFDLHF,FDLHFCRSSI,M KPKRDGYMF,MFLKAESKIM,AESKIMFATL,IMFATLQRSS, FATLQRSSLW,LQRSSLWCLC,PPARVPAVPF,PEPHLALQPL GATA c.1222_122 p.S408f EDFPKNSSFNPAALSRHMSSLSHIS[p.S ALQPLQPHA,AIQPVLWTT,MLTGPPARV,FLKAESKIM,IMF BRCA 3 3insC s 408fs]ALQPLQPHADHAHADAPAIQPV ATLQRS,YMFLKAESK,KIMFATLQR,SMLTGPPAR,HFCRSSI LWTTPPLQHGHRHGLEPCSMLTGPPA MK,MFLKAESKI,MSSLSHISA,SSLSHISAL,CSMLTGPPA,RS RVPAVPFDLHFCRSSIMKPKRDGYMFL SIMKPKR,MKPKRDGY,KAESKIMFA,VPFDLHFCR,GPPAR KAESKIMFATLQRSSLWCLCSNH* VPAV,KPKRDGYMF,FATLQRSSL,DLHFCRSSI,LHFCRSSIM, ESKIMFATL,SHISALQPL,SALQPLQPH,LQPHADHAH,HAH ADAPAI,LQHGHRHGL,RHGLEPCSM,PARVPAVPF,PAVPF DLHF,LKAESKIMF,ATLQRSSLW,LQRSSLWCL,AESKIMFAT, ADAPAIQPV,APAIQPVLW,SMLTGPPARV,YMFLKAESKI,T LQRSSLWCL,HMSSLSHISA,CSMLTGPPAR,LHFCRSSIMK,F CRSSIMKPK,IMKPKRDGYM,GYMFLKAESK,SIMKPKRDGY, TTPPLQHGHR,AVPFDLHFCR,MSSLSHISAL,HADAPAIQPV, QPVLWTTPPL,KPKRDGYMFL,DLHFCRSSIM,MFATLQRSS L,FLKAESKIMF,LSHISALQPL,ADAPAIQPVL,HRHGLEPCSM, ARVPAVPFDL,VPAVPFDLHF,FDLHFCRSSI,MKPKRDGYM F,MFLKAESKIM,AESKIMFATL,IMFATLQRSS,FATLQRSSL W,LQRSSLWCLC,PPARVPAVPF GATA c.1223_122 p.S408f EDFPKNSSFNPAALSRHMSSLSHIS[p.S ALQPLQPFIA,AIQPVLWTT,MLTGPPARV,FLKAESKIM,IMF BRCA 3 4insT s 408fs]ALQPLQPHADHAHADAPAIQPV ATLQRS,YMFLKAESK,KIMFATLQR,SMLTGPPAR,HFCRSSI LWTTPPLQHGHRHGLEPCSMLTGPPA MK,MFLKAESKI,MSSLSHISA,SSLSHISAL,CSMLTGPPA,RS RVPAVPFDLHFCRSSIMKPKRDGYMFL SIMKPKR,IMKPKRDGY,KAESKIMFA,VPFDLHFCR,GPPAR KAESKIMFATLQRSSLWCLCSNH* VPAV,KPKRDGYMF,FATLQRSSL,DLHFCRSSI,LHFCRSSIM, ESKIMFATL,SHISALQPL,SALQPLQPH,LQPHADHAH,HAH ADAPAI,LQHGHRHGL,RHGLEPCSM,PARVPAVPF,PAVPFDLH F,LKAESKIMF,ATLQRSSLW,LQRSSLWCL,AESKIMFAT, ADAPAIQPV,APAIQPVLW,SMLTGPPARV,YMFLKAESKI,T LQRSSLWCL,HMSSLSHISA,CSMLTGPPAR,LHFCRSSIMK,F CRSSIMKPK,IMKPKRDGYM,GYMFLKAESK,SIMKPKRDGY, TTPPLQHGHR,AVPFDLHFCR,MSSLSHISAL,HADAPAIQPV, QPVLWTTPPL,KPKRDGYMFL,DLHFCRSSIM,MFATLQRSS L,FLKAESKIMF,LSHISALQPL,ADAPAIQPVL,HRHGLEPCSM, ARVPAVPFDL,VPAVPFDLHF,FDLHFCRSSI,MKPKRDGYM F,MFLKAESKIM,AESKIMFATL,IMFATLQRSS,FATLQRSSL W,LQRSSLWCC,PPARVPAVPF GATA c.1290_129 p.S430f ISPFSHSSHMLTTPTPMHPPSSLSF[p.S4 MLTGPPARV,FLKAESKIM,IMFATLQRS,YMFLKAESK,KIMF BRCA 3 1insT s 30fs]WTTPPLQHGHRHGLEPCSMLTG ATLQR,SMLTGPPAR,HFCRSSIMK,MFLKAESKI,LSFWTTPP PPARVPAVPFDLHFCRSSIMKPKRDGY L,CSMLTGPPA,RSSIMKPKR,IMKPKRDGY,KAESKIMFA,VP MFLKAESKIMFATLQRSSLWCLCSNH* FDLHFCR,GPPARVPAV,KPKRDGYMF,FATLQRSSL,DLHFC RSSI,LHFCRSSIM,ESKIMFATL,LQHGHRHGL,RHGLEPCSM, PARVPAVPF,PAVPFDLHF,LKAESKIMF,ATLQRSSLW,LQR SSLWCL,AESKIMFAT,HPPSSLSFW,SLSFWTTPPL,SMLTGP PARV,YMFLKAESKI,TLQRSSLWCL,CSMLTGPPAR,MHPPS SLSFW,LHFCRSSIMK,FCRSSIMKPK,IMKPKRDGYM,GYMF LKAESK,SIMKPKRDGY,TTPPLQHGHR,AVPFDLHFCR,KPK RDGYMFL,DLHFCRSSIM,MFATLQRSSL,FLKAESKIMF,HR HGLEPCSM,ARVPAVPFDL,VPAVPFDLHF,FDLHFCRSSI,M KPKRDGYMF,MFLKAESKIM,AESKIMFATL,IMFATLQRSS, FATLQRSSLW,LQRSSLWCLC,PPARVPAVPF GATA c.1301_130 p.H434 FSHSSHMLTTPTPMHPPSSLSFGPH[p. MLTGPPARV,FLKAESKIM,IMFATLQRS,YMFLKAESK,KIMF BRCA 3 2insC fs H434fs]PPLQHGHRHGLEPCSMLTGPP ATLQR,SMLTGPPAR,HFCRSSIMK,MFLKAESKI,CSMLTGP ARVPAVPFDLHFCRSSIMKPKRDGYMF PA,RSSIMKPKR,IMKPKRDGY,KAESKIMFA,VPFDLFIFCR,G LKAESKIMFATLQRSSLWCLCSNH* PPARVPAV,KPKRDGYMF,FATLQRSSL,DLHFCRSSI,LHFCR SSIM,ESKIMFATL,LSFGPHPPL,LQHGHRHGL,RHGLEPCS M,PARVPAVPF,PAVPFDLFIF,LKAESKIMF,ATLQRSSLW,L QRSSLWCL,AESKIMFAT,SLSFGPHPPL,SMLTGPPARV,YM FLKAESKI,TLQRSSLWCL,CSMLTGPPAR,LHFCRSSIMK,FCR SSIMKPK,IMKPKRDGYM,GYMFLKAESK,SIMKPKRDGY,A VPFDLHFCR,KPKRDGYMFL,DLHFCRSSIM,MFATLQRSSL, FLKAESKIMF,HRHGLEPCSM,ARVPAVPFDL,VPAVPFDLHF, FDLHFCRSSI,MKPKRDGYMF,MFLKAESKIM,AESKIMFAT L,IMFATLQRSS,FATLQRSSLW,LQRSSLWCLC,PPARVPAVPF GATA c.1304_130 p.H435 HSSHMLTTPTPMHPPSSLSFGPHHP[p. MLTGPPARV,FLKAESKIM,IMFATLQRS,YMFLKAESK,KIMF BRCA 3 5insC fs H435fs]LQHGHRHGLEPCSMLTGPPAR ATLQR,SMLTGPPAR,HFCRSSIMK,MFLKAESKI,CSMLTGP VPAVPFDLHFCRSSIMKPKRDGYMFLK PA,RSSIMKPKR,IMKPKRDGY,KAESKIMFA,VPFDLHFCR,L AESKIMFATLQRSSLWCLCSNH* SFGPFIHPL,GPPARVPAV,KPKRDGYMF,FATLQRSSL,DLHF CRSSI,LHFCRSSIM,ESKIMFATL,LQHGHRHGL,RHGLEPCS M,PARVPAVPF,PAVPFDLHF,LKAESKIMF,ATLQRSSLW,L QRSSLWCL,HPLQHGHRH,AESKIMFAT,SLSFGPHHPL,SML TGPPARV,YMFLKAESKI,LQRSSLWCL,CSMLTGPPAR, LHFCRSSIMK,FCRSSIMKPK,IMKPKRDGYM,GYMFLKAESK,SI MKPKRDGY,AVPFDLHFCR,KPKRDGYMFL,DLHFCRSSIM, MFATLQRSSL,FLKAESKIMF,HRHGLEPCSM,ARVPAVPFDL, VPAVPFDLHF,FDLFIFCRSSI,MKPKRDGYMF,MFLKAESKI M,AESKIMFATL,IMFATLQRSS,FATLQRSSLW,LQRSSLWC LC,PPARVPAVPF GATA c.1329G>T p.M44 TTPTPMHPPSSLSFGPHHPSSMVTA[p. HPSSMVTAI LUAD 3 3I M443I]IG* GATA c.983_984 p.L328f RRLSAARRAGTSCANCQTTTTTLWR[p. CLQCLWALL,QWGPCLQCL,TTTTTLWRL,WALLQASQY,EE BRCA 3 insCTGGAG s L328fs]LEEECQWGPCLQCLWALLQAS CQWGPCL,QWGPCLQCLW,LWALLQASQY,QTTTTTLWRL, G QY* CQWGPCLQCL,LQCLWALLQA GBP7 c.1292_129 p.G431 QAELKRLSELLTESISRGTFFVPGG[p.G4 FVPGGAQYL,AQYLLRSKK,GAQYLLRSK,FFVPGGAQY,VPG STAD 3insG fs 31fs]AQYLLRSKKED* GAQYLL,FVPGGAQYLL,GAQYLLRSKK,FFVPGGAQYL,TFFV PGGAQY GCDH c.1167de|G p.L389f VSLLKRNNCGKALDIARQARDMLGG[p. MLGGMGFLT,RDMLGGMGF,GGMGFLTSI,RQARDMLGG STAD s L389fs]MGFLTSIT* M,RDMLGGMGFL GCDH c.244C>T p.R82C EEQLTTDEILIRDTFRTYCQERLMP[p.R8 RLMPCILLA,MPCILLANR,QERLMPCIL,LMPCILLANR,CQE LUAD 2C]CILLANRNEVFHREIISEMGELGVLG RLMPCIL,QERLMPCILL GDAP c.919A>G p.T307 RVLKRKTFNKVLGHVNNILISAVLP[p.T3 ILISAVLPA,LISAVLPAA,AVLPAAFRV,VLPAAFRVA,SAVLPA BRCA 1 A 07A]AAFRVAKKRAPKVLGTTLVVGLLA AFR,LPAAFRVAK,ISAVLPAAF,ILISAVLPAA,VLPAAFRVAK,I GV SAVLPAAFR,AVLPAAFRVA,SAVLPAAFRV,LISAVLPAAF GDF5 c.315_316i p.E105f GQTGGLTQPKKDEPKKLPPRPGGPE[p. RICPQLLPA,ASRRQGTPK,QARTPSPNK,RTASRRQGT,KSRI TGCT nsA s E105fs]TQARTPSPNKAGYSPDCDPKRT CPQLL,HTPRVHALA,SPTPHHTPR,HALAVQDAV,APTRAQ ASRRQGTPKSRICPQLLPAEEGQGARA GAV,TPRVHALAV,RQGTPKSRI,RAQGAVSPT,AQGAVSPT PTRAQGAVSPTPHHTPRVHALAVQDA P,HHTPRVHAL,TPSPNKAGY,AEEGQGARA,LLPAEEGQGA, VRC* TQARTPSPNK,TASRRQGTPK,QARTPSPNKA,AGYSPDCDP K,ASRRQGTPKS,KSRICPQLLP,RVHALAVQDA,RTPSPNKA GY,HALAVQDAVR,HTPRVHALAV,TPKSRICPQL,SPTPHHT PRV,SRICPQLLPA,AQGAVSPTPH GDPD c.1779_178 p.G593 SVCSDNSYDTYANSTATPVGPRGGG[p. GPRGGGQPH,EPRRAGGSV,QPPCGLQPL,HQDPHRAEW, KIRP 5 0insC fs G593fs]QPHQDPHRAEWALAEDMSV AEWALAEDM,WALAEDMSV,AEDMSVPPV,RAGGSVSEL, PPVPDTEAGEPRRAGGSVSELGVLWER WERAPQPPC,LQPLVSRSL,SELGVLWER,DPHRAEWAL,AL APQPPCGLQPLVSRSLS* AEDMSVPP,GLQPLVSRSL,RAEWALAEDM,RRAGGSVSEL, AEWALAEDMS,SELGVLWERA,QPPCGLQPLV GEM c.803G>T p.R268 RDSKEKNERRLAYQKRKESMPRKAR[p. RLFWGKIVA,SMPRKARLF,RKARLFWGK,KARLFWGKI,LF LUAD L R268L]LFWGKIVAKNNKNMAFKLKSKS WGKIVAK,MPRKARLFW,ESMPRKARL,RLFWGKIVAK,SM CHDL PRKARLFW,KARLFWGKIV,MPRKARLFWG,KESMPRKARL, RKARLFWGKI GEN1 c.1526C>T p.S509 VMSFQSHMTLKPTCEIFHKQNSKLN[p. HKQNSKLNL,SKLNLGISP,LGISPDPTL,KQNSKLNLGI,FHKQ UCEC L S509L]LGISPDPTLPQESISASLNSLLLPK NSKLNL N GFM1 c.49_50ins p.A17fs MRLLGAAAVAALGRGRAP[p.A17fs]RL RLPRLAEEA,ALGRGRAPR,RGRAPRLPR,APRLPRLAE,AALG KICH C PRLAEEAG* RGRAPR,RGRAPRLPRL GFRAL c.922C>A p.Q308 LGTVLQVQCTCRTITQSEESLCKIF[p.Q3 KIFKHMLHR,IFKHMLHRK,SLCKIFKHM,SLCKIFKHML,KIFK LUAD K 08K]KHMLHRKSCFNYPTLSNVKGMAL HMLHRK,KHMLHRKSCF YTR GGA2 c.188C>T p.A63V MSEQDWSAIQNFCEQVNTDPNGPTH[p. HVPWLLAHK,HVPWLLAH,VPWLLAHKI,GPTHVPWLL,N UCEC A63V]VPWLLAHKIQSPQEKEALYALT TDPNGPTHV,HVPWLLAHKI,DPNGPTHVPW VLEM GIGYF c.680G>A p.R227 PNFEEGGPTSVGRKHEFIRSESENW[p. ESENWHIFR,SESENWHIF,RSESENWHIF UCEC 2 H R227H]HIFREEQNGEDEDGGWRLAGS RRDGE GIMA c.827de|T p.V276 LLKLKYDEKIKNIREEAERNIFKDV[p.V27 NVSFILPNL,IGFGRCFQK,IFKDVLIGF,CFQKYGIGF,IGFCRN STAD P7 fs 6fs]LIGFGRCFQKYGIGFCRNVSFILPNL VSF,GFGRCFQKY,VLIGFGRCF,VSFILPNLL,LIGFGRCFQK,K L* YGIGFCRNV,IGFGRCFQKY,FQKYGIGFCR,NVSFILPNLL,NI FKDVLIGF,AERNIFKDVL,RCFQKYGIGF,GIGFCRNVSF,IGFC RNVSFI,RNVSFILPNL GIMA c.1630G>T p.A544 SCCEKGDTFFVLVFQLGRFTEEDKT[p.A KTSVAKLEA,FTEEDKTSV,SVAKLEAIF,KTSVAKLEAI,TSVAK KIRP P8 S 544S]SVAKLEAIFGADFTKYAIMLFTRK LEIAF,EEDKTSVAKL ED GIPC3 c.679de|G p.G227 SRSSKCPVEAKVTSGRETLRLRSGG[p.G RLMTCWKAT,RAPRSLHAV,SLRRRFILGR,TCWKATWAF,T STAD fs 227fs]LPQWRKRPVSLRRRHLGRLMTC WAFGTPSW,RLRSGGLPQ,QWRKRPVSL,RKRPVSLRR,RRR WKATWAFGTPSWRPPWWRRPRRQR HLGRLM,LGRLMTCWK,CWKATWAFG,SWRPPWWRR,RP APRSLHAV* RRARAPR,RQRAPRSLH,WAFGTPSWR,RPPWWRRPR,MT CWKATWA,LPQWRKRPV,TLRLRSGGL,LRSGGLPQW,LMT CWKATW,RRQRAPRSL,TPSWRPPWW,LMTCWKATWA, GLPQWRKRPV,SLRRRHLGRL,HLGRLMTCWK,RSGGLPQ WRK,VSLRRRHLGR,RLMTCWKATW,MTCWKATWAF,RLR SGGLPQW,QWRKRPVSLR,RKRPVSLRRR,SWRPPWWRRP, WWRRPRRQRA,RQRAPRSLHA,TWAFGTPSWR,TPSWRP PWWR,RPPWWRRPRR,ETLRLRSGGL,LPQWRKRPVS,RPV SLRRRHL,RPRRQRAPRS,PQWRKRPVSL,LRRRHLGRLM,R HLGRLMTCW,ATWAFGTPSW,FGTPSWRPPW GIT2 c.368G>T p.R123 KVHPNKAEFIRAKYQMLAFVHRLPC[p. CLDDDSVTA,LPCLDDDSV,RLPCLDDDSV,LAFVHRLPCL LUAD L R123L]LDDDSVTAKDLSKQLHSSVRTG NLET GJA1 c.932de|C p.A311 YKLVTGDRNNSSCRNYNKQASEQNW[p. SLTPMHSLL,LISPMITRI,KQASEQNWV,LLISPMITR,SPMIT KIRC fs p.A311fs]VITVQNKIEWGRREAPSLTP RILK,QASEQNWVI,WVITVQNKI,REAPSLTPM,SEQNWVIT MHSLLISPMITRILKN* V,WGRREAPSL,MHSLLISPM,IEWGRREAP,KQASEQNWVI, SLTPMHSLLI,LLISPMITRI,LISPMITRIL,SLLISPMITR,ISPMI TRILK,NWVITVQNKI,TVQNKIEWGR,APSLTPMHSL,RREA PSLTPM,REAPSLTPMH,PMHSLLISPM,MHSLLISPMI,IEW GRREAPS GJB3 c.479G>A p.R160 LIFKLIIEFLFLYLLHTLWHGFNMP[p.R16 NMPHLVQCA,HLVQCANVA,MPHLVQCAN,LWHGFNMP GBM H 0H]HLVQCANVAPCPNIVDCYIARPTEK HL,MPHLVQCANV K GJB4 c.64C>A p.R22S MNWAFLQGLLSGVNKYSTVLS[p.R22S] VLSSIWLSV,SIWLSVVFI,LSSIWLSVV,KYSTVLSSI,SSIWLSV LUAD SIWLSVVFIFRVLVYVVAAEEVWDDE VF,STVLSSIWL,NKYSTVLSS,YSTVLSSIW,TVLSSIWLSV,VLS SIWLSVV,KYSTVLSSIW,SIWLSVVFIF,SSIWLSVVFI,LSSIWL SVVF,NKYSTVLSSI,YSTVLSSIWL GLB1L c.1221C>G p.I407 KMPYEPLTPVLYLSLWDALKYLGEP[p.I ALKYLGEPM,EPMKSEKPI,MKSEKPINM,ALKYLGEPMK,DA LUAD 2 M 407M]MKSEKPINMENLPVNGGNGQS LKYLGEPM FGYIL GLI1 c.815de|G p.W27 QEQLVHHINSEHIHGERKEFVCHWG[p. KEFVCHWGA,KEFVCHWGAA STAD 2fs W272fs]AAPGS* GLI3 c.2993C>T p.P998 VHAPRRCSDGGAHGYGRRHLQPHDA[p. ALGHGVRRA,DALGHGVRR,RHLQPHDAL,RRHLQPHDAL ACC L p.P998L]LGHGVRRASDPVRTGSEGLAL PRVPR GLI3 c.3098de|C p.P103 PVRTGSEGLALPRVPRFSSLSSCNP[p.P1 AVSCFRITR,SSLSSCNPR,SLSSCNPRR,SCNPRRWPR,RWPR STAD 3fs 033fs]RRWPRPRRSAVSCFRITRGPRAA PRRSA,RRSAVSCFR,RSAVSCFRI,CFRITRGPR,ITRGPRAAS, SPETSTRPPVLPASPRTSPWSP* STRPPVLPA,NPRRWPRPR,WPRPRRSAV,RPRRSAVSC,GP RAASPET,LPASPRTSP,FSSLSSCNPR,SSLSSCNPRR,SSCNP RRWPR,SAVSCFRITR,RWPRPRRSAV,CFRITRGPRA,ITRGP RAASP,RAASPETSTR,STRPPVLPAS,CNPRRWPRPR,SCFRI TRGPR,WPRPRRSAVS,RPRRSAVSCF,SPETSTRPPV,LPASP RTSPW,RRWPRPRRSA,RRSAVSCFRI,FRITRGPRAA GLIPR c.276de|A p.G92fs IPRGSNLRFMTWDVALSRTARAWGK[p. HVQKLDILY,SILNFMVLV,ALKMNLLQV,KMNLLQVLL,LLQ STAD 1L2 G92fs]NVCLRIIFIYKMYKWSILNFMVL VLLSEV,KMAVALETV,LIIFSLFGT,TLTKLWLL,KLVVLLLHV, VKICGSALKMNLLQVLLSEVGMQRRKC VLLLHVQKL,YMQQFSYAT,VLVKICGSA,CLRIIFIYK,IIFIYKM TILKMAVALETVLIIFSLFGTTLTKLVVLLL YK,KMYKWSILN,ILNFMVLVK,SLFGTTLTK,VVLLLHVQK,IL HVQKLDILYMQQFSYATMRQEEH* YMAQFSY,QQFSYATMR,IFIYKMYKW,IYKMYKWSI,MYK WSILNF,KWSILNFMV,TVLIIFSLF,IFSLFGTTL,LYMQQFSYA, TARAWGKNV,MQRRKCTIL,QRRKCTILK,RIIFIYKMY,LLSE VGMQR,CTILKMAVA,ETVLIIFSL,LVKICGSAL,YKMYKWSIL, GMQRRKCTI,VQKLDILYM,MQQFSYATM,RAWGKNVCL, KNVCLRIIF,LRIIFIYKM,YKWSILNFM,WSILNFMVL,KICGSA LKM,LKMNLLQVL,LQVLLSEVG,RRKCTILKM,LKMAVALET, MAVALETVL,VALETVLII,ALETVLIIF,LHVQKLDIL,LDILYMQ QF,FIYKMYKWSI,YKWSILNFMV,WSILNFMVLV,ILNFMVL VKI,NLLQVLLSEV,KMAVALETVL,VLIIFSLFGT,IIFSLFGTTL, SLFGTTLTKL,TLTKLVVLLL,ILYMQQFSYA,YMQQFSYATM, VLVKICGSAL,ALKMNLLQVL,RIIFIYKMYK,KMYKWSILNF,S ILNFMVLVK,LVKICGSALK,MQRRKCTILK,FSLFGTTLTK,RA WGKNVCLR,LVVLLLFIVQK,MQQFSYATMR,AWGKNVCLR I,IYKMYKWSIL,MYKWSILNFM,KWSILNFMVL,VALETVLIIF, ETVLIIFSLF,LYMQQFSYAT,RTARAWGKNV,CLRIIFIYKM,D ILYMQQFSY,CTILKMAVAL,MAVALETVLI,VGMQRRKCTI, GMQRRKCTIL,LQVLLSEVGM,ARAWGKNVCL,GKNVCLRII F,LRIIFIYKMY,IIFIYKMYKW,VKICGSALKM,LKMNLLQVLL, QRRKCTILKM,LKMAVALETV,LETVLIIFSL,LHVQKLDILY,HV QKLDILYM,KLDILYMQQF,QQFSYATMRQ GLOD c.667_668i p.Q223 KLELQGVKGGVDHAAAFGRIAFSCP[p. IAFSCPPER,NSTGGHSGR,HPRESNSTG,RESNSTGGH,CPP LUAD 4 nsC fs Q223fs]PERVARLRRLDEKGEPEDSDSP ERVARL,RIAFSCPPER,VARLRRLDEK,FSCPPERVAR,IAFSCP GEPGHPRESNSTGGHSGRP* PERV GLRA3 c.1360C>A p.L454I DTISRACFPLAFLIFNIFYWVIYKI[p.L454 FYWVIYKII,IFYWVIYKII,IYKIIRHEDI,FYWVIYKIIR CRC I]IRHEDIHQQQD* GLRA3 c.396C>A p.F132 AYSEYPDDSLDLDPSMLDSIWKPDL[p.F LLFANEKGA,SIWKPDLLF,IWKPDLLFA,DSIWKPDLL,SIWK CRC L 132L]LFANEKGANFHEVTTDNKLLRIFK PDLLFA,LFANEKGANF NG GLT8D c.533C>T p.A178 IYLDDDVIVQGDIQELYDTTLALGH[p.A TLALGHVAA,DTTLALGHV,TTLALGHVA,LALGHVAAF,DTT GBM 2 V 178V]VAAFSDDCDLPSAQDINRLVGLQ LALGHVA,TTLALGHVAA,TLALGHVAAF NTY GLTSC c.1166A>G p.Q389 RHQELFRLRGIKAQVALRLAELARR[p.Q RRRRRQARR,ELARRRRRR,RLAELARRR,LARRRRRRQA,RR ACC R2 R 389R]RRRRQARREAEADKPRRLGRLKY RRRRQARR,RLAELARRRR QAP GLYR1 c.1139_114 p.G380 CYVDMSTVDADTVTELAQVIVSRGG[p. SPRLRESAA,GALSGSPRL,RGGALSGSPR,QVIVSRGGAL,SP STAD 0insG fs G380fs]ALSGSPRLRESAAV* RLRESAAV GNA1 c.598A>G p.R200 KYFLDNLDKLGEPDYIPSQQDILLA[p.R2 ILLAGRPTK,SQQDILLAG,LLAGRPTKGI BLCA 3 G 00G]GRPTKGIHEYDFEIKNVPFKMVDV GG GNAO c.848C>A p.P283 KWFTDTSIILFLNKKDIFEEKIKKS[p.P28 KIKKSQLTI,QLTICFPEY,KKSQLTICF,KIKKSQLTIC,SQLTICFP LUAD 1 Q 3Q]QLTICFPEYTGPSAFTEAVAYIQAQY EY,IKKSQLTICF,FEEKIKKSQL GNAS c.2530C>T p.R844 QYFLDKIDVIKQADYVPSDQDLLRC[p.R CCVLTSGIF,RCCVLTSGIF LIHC C 844C]CVLTSGIFETKFQVDKVNFHMFD VGG GNAS c.2531G>A p.R844 QYFLDKIDVIKQADYVPSDQDLLRC[p.R LLRCHVLTS,CHVLTSGIF,RCHVLTSGIF PAAD H 844H]HVLTSGIFETKFQVDKVNFHMFD VGG GNB1 c.239T>C p.I80T LAKIYAMHWGTDSRLLVSASQDGKL[p. LTIWDSYTT,SQDGKLTIW,GKLTIWDSY,TIWDSYTTNK,AS CLL I80T]TIWDSYTTNKVHAIPLRSSWVMT QDGKLTIW CAY GNG1 c.202de|A p.T68fs CEEHARSDPLLIGIPTSENPFKDKK[p.T6 KLASSYSGI,ASSYSGIEK,LLASSQQRK,KDKKLASSY,KKLASS STAD 2 8fs]LASSYSGIEKQLLASSQQRKL* YSG,KQLLASSQQ,IEKQLLASS,LLASSQQRKL,QLLASSQQR K,LASSYSGIEK,SYSGIEKQLL,FKDKKLASSY,KKLASSYSGI,SS YSGIEKQL,SENPFKDKKL GNPN c.162de|T p.F54fs AISPTHPGEGLVLRPLCTADLNRGF[p.F RGFLRYWVS,DLNRGFLRY,TADLNRGFLR,CTADLNRGFL,A STAD AT1 54fs]LRYWVS* DLNRGFLRY GNPT c.3566G>A p.R118 VKAVLRDFYESMFPIPSQFELPREY[p.R EYQNRFLHM,LPREYQNRF,REYQNRFLH,YQNRFLHMH,LP UCEC AB 9Q 1189Q]QNRFLHMHELQEWRAYRDKL REYQNRFL,REYQNRFLHM,SQFELPREYQ KFWTHC GOLG c.4608G>T p.Q153 KKESNLETELKSQTARIMELEDHIT[p.Q1 MELEDHITH,HKTIEIESL,LEDHITHKTI CRC A4 6H 536H]HKTIEIESLNEVLKNYNQQKDIEH KE GOLG c.1474C>A p.L492I ELEELRHEKEMQREEIQKLMGQIHQ[p. KLMGQIHQI,KLMGQIHQIR,HQIRSELQDM,QKLMGQIHQI, KIRC A5 L492I]IRSELQDMEAQQVNEAESAREQ GQIHQIRSEL LQDL G0T2 c.1063C>T p.R355 ILNTPDLRKQWLQEVKVMADRIIGM[p. RIIGMWTQL,IIGMWTQLV,WTQLVSNLK,MWTQLVSNL, PRAD W R355W]WTQLVSNLKKEGSTHNWQHI MADRIIGMW,RIIGMWTQLV,GMWTQLVSNL,MWTQLVS TDQIGM NLK,WTQLVSNLKK,VMADRIIGMW GP2 c.122C>T p.S41L LALVSCILTQASAVQRGYGNPIEAS[p.S4 NPIEASLYG,YGNPIEASLY,NPIEASLYGL,IEASLYGLDL CRC 1L]LYGLDLDCGAPGTPEAHVCFDPCQ NY GPAT c.629_630i p.K210f FLARLKGQDPGAPQLQSESKPPKKK[p. EAERGGRSY,KEAERGGRSY,AERGGRSYSI PRAD CH4 nsA s K210fs]EKEKEAERGGRSYSI* GPAT c.629de|A p.K210f AFLARLKGQDPGAPQLQSESKPPKK[p. MQMRSTQNM,QMRSTQNML,MLSRTSEKA,NMLSRTSEK, STAD CH4 s K210fs]RKRKGGRKRRKKLQHLKGMM QMKERVQLK,RSTQNMLS,RVQLKGMRR,KRKRKGGRK, QMRSTQNMLSRTSEKARRRKGDIKKER KGGRKRRKK,RRKKLQHLK,LSRTSEKAR,RTSEKARRR,KARR SQMKERVQLKGMRRRTLQEQVGLGN RKGDI,RRRKGDIKK,KGMRRRTLQ,GMRRRTLQE,HLKGM * MQMR,LKGMRRRTL,KKLQHLKGM,QHLKGMMQM,GM MQMRSTQ,SQMKERVQL,KERVQLKGM,RTLQEQVGL,M QMRSTQNML,MMQMRSTQNM,SQMKERVQLK,RTSEKA RRRK,KKRKRKGGRK,KRKGGRKRRK,KRRKKLQHLK,QMRS TQNMLS,QNMLSRTSEK,LSRTSEKARR,KARRRKGDIK,RSQ MKERVQL,RVQLKGMRRR,MLSRTSEKAR,QLKGMRRRTL, LQHLKGMMQM,RKRRKKLQHL,RKKLQHLKGM,KKLQHLK GMM,MKERVQLKGM,KERSQMKERV GPC5 c.1040G>T p.R347 LVNDAVLQAHLNGQKLLEQVNRICG[p. EQVNRICGL,QVNRICGLPV,VNRICGLPVR,LEQVNRICGL LUSC L R347L]LPVRTPTQSPRCSFDQSKEKHG MKTT GPC6 c.640G>A p.A214 CVSKYTDQLKPFGDVPRKLKIQVTR[p.A VTRTFIAAR,RTFIAARTF,KIQVTRTFI,QVTRTFIAA,TFIAART CRC T 214T]TFIAARTFVQGLTVGREVANRVS FV,LKIQVTRTF,IQVTRTFIA,RTFIAARTFV,KLKIQVTRTF,KI KVS QVTRTFIA,VTRTFIAART,QVTRTFIAAR,LKIQVTRTFI,IQVT RTFIAA,TRTFIAARTF GPLD c.2150G>A p.R717 TRMYALTSDAQPLLLSTFSGDRRFS[p.R SQFGGVLHL,SGDRRFSQF,RRFSQFGGV,RFSQFGGVL,FSG CRC 1 Q 717Q]QFGGVLHLSDLDDDGLDEIIMAA DRRFSQF,RRFSQFGGVL,FSQFGGVLHL,SQFGGVLHLS PLR GPM6 c.149C>T p.A50V IPYASLIATILLYAGVALFCGCGHE[p.A5 VLSGTVNIL,EVLSGTVNI,ALFCGCGFIEV,EVLSGTVNIL,HEV KIRC A 0V]VLSGTVNILQTYFEMARTAGDTLDV LSGTVNI F GPNM c.522C>G p.I174 GQSHHNVFPDGKPFPHHPGWRRWNF FMYVFHTLG,RRWNFMYVF,NFMYVFHTL,GWRRWNFMY, LUAD B M [p.I174M]MYVFHTLGQYFQKLGRCSV RWNFMYVFH,MYVFHTLGQY,GWRRWNFMYV,RWNFM RVSVNTA YVFHT,HPGWRRWNFM,WNFMYVFHTL,WRRWNFMYVF, FMYVFHTLGQ GPNM c.910de|T p.C3fs MECL[p.C3fs]LFPGISAPGCKIAT* LLFPGISQP,MECLLFPGI,LLFPGISQPG,MECLLFPGIS TGCT B C GPR1 c.1327A>G p.R443 TALPLNFSRKFIDWKGIPVNKSQLK[p.R KGGYSYQIK,SQLKGGYSY,LKGGYSYQI,GGYSYQIKM,QLKG CLL 10 G 443G]GGYSYQIKMCPQNTSIPIRGRVLI GYSYQI,VNKSQLKGGY,KSQLKGGYSY,SQLKGGYSYQ,KGG GS YSYQIKM GPR1 c.3848C>A p.S128 KDQMTISLGKTPRTMEVTEMSPSKN[p. KNYFISYSR,MSPSKNYFI,PSKNYFISY,EMSPSKNYF,TEMSP UCEC 12 3Y S1283Y]YFISYSRGTPSLEMTDTGFPETT SKNY,VTEMSPSKNY,EMSPSKNYFI,SPSKNYFISY,TEMSPSK KIS NYF GPR1 c.1889T>C p.L630 PRTPHCVGKKVPQPVGAADLAPDTS[p. DLAPDTSPCR CLL 23 P L630P]PCRKEGSSASRSCRPGPGHLTRR EED GPR1 c.338G>A p.R113 LSNNKISELKNGSFSGLSLLERLDL[p.R1 LQNNLISSI,LERLDLQNNL CRC 25 Q 13Q]QNNLISSIDPGAFWGLSSLKRLDLT N GPR1 c.718G>T p.G240 KISKMSLANIYLESKGSSVCQVTAI[p.G2 QVTAICVTV,ICVTVILLY,TAICVTVIL,CQVTAICVT,CQVTAIC LUAD 37B C 40C]CVTVILLYTSRACYNLFILSFSQNKS VTV,AICVTVILLY,SVCQVTAICV,QVTAICVTVI,TAICVTVILL GPR1 c.2262C>A p.F754 PVPSGCASLSSQHSYFDTESSSSDE[p.F7 SSSDELFCR,LFCRCHRPY,TESSSSDEL,SSSSDELFCR,ELFCR CRC 56 L 54L]LFCRCHRPYCEICFQSSSDSSDSGTS CHRPY,TESSSSDELF GPR1 c.1696G>A p.D566 LIGWTSSVCQNLEKQISLIGQGKTS[p.D KTSNHLIFN,TSNHLIFNM,GQGKTSNHL,GKTSNHLIF,KTSN CRC 58 N 566N]NHLIFNMCLIDRWDYMTAVAEF HLIFNM,GQGKTSNHLI,QGKTSNHLIF LFLL GPR1 c.2284C>A p.P762 NPHLQKKRCSKKGLGRSIMRRITEI[p.P7 RITEITETV,RRITEITETV LUAD 58 T 62T]TETVSRQCSKEDKEGADHGTAKGT AL GPR1 c.1550de|G p.G517 AEAKINLFGEEALPGVLVTARTVPG[p.G TARTVPGAA,VTARTVPGA,TVPGAASGA,VPGAASGAA,LV STAD 61 fs 517fs]AASGAAEAAELL* TARTVPGA,RTVPGAASGA,VTARTVPGAA,TVPGAASGAA GPR2 c.647G>A p.R216 FTLFIVMMLYAPAALIVCFTYFNIF[p.R2 FTYFNIFHI,TYFNIFHIC,CFTYFNIFHI,IFHICQQHTK,FTYFNI CRC 1 H 16H]HICQQHTKDISERQARFSSQSGET FHIC GE GPR6 c.106_165d p.AAAA AAMNASAASLNDSQVVVVAAEGAAA[p. VAAEGAAAL,AEGAAALGA,VVAAEGAAAL,AEGAAALGAG PAAD e|GCGGCG ATAAG AAAAATAAGGPDTGEWGPPA36de|] GCGGCGGC GPDTG LGAGGGANGSLELSSQLSAGPPGLLLP CACAGCAG EWGPP AVNPWDVLLCVSGTVIAGENALVVALI CAGGGGG A36de| ASTPALRTPMFVLVGSLATADLLAGCGL GCCGGACA ILH CGGGCGAA TGGGGACC CCCTGCT GPR9 c.12424C>T p.R414 RFTIQLISIDEVEISPVKGSASIII[p. ASIIIWGDK,SIIIWGDKR,KGSASIIIW,SASIIIWGDK,VKGSA CRC,UCEC 8 2W R4142W]WGDKRASGEVGIAPSSRHILIGEPSA SIIIW GPR9 c.12919G>T p.G430 QRVNITIIRSSGDFGHVRLWYKTMS[p. WTAEAGLDF,KTMSWTAEA,RLWYKTMSW,WYKTMSWT LUAD 8 7W G4307W]WTAEAGLDFVPAAGELLFEA A,MSWTAEAGL,TMSWTAEAGL,WTAEAGLDFV,RLWYKT GEMRKS MSWT,SWTAEAGLDF,VRLWYKTMSW,LWYKTMSWTA,Y KTMSWTAEA GPR9 c.18455A>T p.Y615 AYRHFWMLVLFVIFNSLQGLYVFMV[p. YVFMVFFIL,QGLYVFMVF,LYVFMVFFI,VFFILHNQM,GLYV CLL 8 2F Y6152F]FFILHNQMCCPMKASYTVEM FMVFF,GLYVFMVFFI,LQGLYVFMVF,QGLYVFMVFF,LYVF NGHPGP MVFFIL,MVFFILHNQM GPRA c.2117C>T p.S706 KEPCMYPAGGGSWKSRPEEEEDIVN[p. IVNLWFWSR,VNLWFWSRK,NLWFWSRKY,EEEDIVNLW,E HNSC SP1 L S706L]LWFWSRKYTKPEAIIGSWLWAT EDIVNLWF,EEEEDIVNL,IVNLWFWSRK,LWFWSRKYTK,V EESN NLWFWSRKY,DIVNLWFWSR,EEEDIVNLWF,EEDIVNLWF W GPRC c.88G>A p.V30I VPDGCRNGLKSKYYRLCDKAEAWGI[p. IILETVATA,AWGIILETV,EAWGIILET,KAEAWGIIL,AEAWGI CRC 5A V30I]ILETVATAGVVTSVAFMLTLPILVC ILE,ILETVATAGV,GIILETVATA,EAWGIILETV,AEAWGIILET K GPRIN c.693_716d p.231_ KEDLGSLGKVDPLCSSKTYTVSPRK[p.23 TVSPRKVDPV,KTYTVSPRKV KIRC 1 e|GAAGGA 239RKE 1_239RKEDPGSLR>R]VDPVSSDKVDP GGATCCTG DPGSL VFPRKEEPRYSGKEHPVSSEKVAPTSAE GGTCTTTG R>R KVDLVLSGKR AG GPRIN c.1337G>A p.R446 APASEDSLSVEGRRGPLRAVMQSLR[p. MQSLRHPSC ACC 2 H R446H]HPSCCGCSGAAPE* GPRIN c.298A>C p.T100 ARASGPKARPSAGGHWWSSTVGNVS[p. STVGNVSPM,SSTVGNVSPM CESC 2 P T100P]PMGGSDLCRLRAPSAAAMQ RSHSDLV GPRIN c.721G>A p.V241 KAAEQLATTTCHALPPAALLCGMRE[p. ALLCGMREM,LLCGMREMR,REMRAGGCC,AALLCGMRE ACC 2 M V241M]MRAGGCCHALPATGILAFPKL M,REMRAGGCCH,MRAGGCCHAL VASVS GPRIN c.1898de|G p.R633f PSDPMGDSSPGSGKKTPSRSVKASP[p. ASASSSRSK,RSVKASPPG,KASPPGPAA,SPPGPAASA,AASA HNSC 3 s R633fs]PGPAASASSSRSKS* SSSRSK,SVKASPPGPA,VKASPPGPAA GPT2 c.29G>C p.R10P MQRAAALVR[p.R10P]PGCGPRTPSS LVRPGCGPR,RPGCGPRTPS,MQRAAALVRP TGCT WGRSQSSAAAEASAVL GRAM c.369C>G p.I123 DFLLQGRLYISPNWLCFHASLFGKD[p.I SLFGKDMKV,ASLFGKDMK,HASLFGKDM,KDMKVVIPV,SL CESC D2 M 123M]MKVVIPVVSVQMIKKHKMARLL FGKDMKVV,HASLFGKDMK,FHASLFGKDM,KDMKVVIPV PNGL V,MKVVIPVVSV GRAP c.207G>T p.E69D GYVPKNFIDIQFPKWFHEGLSRHQA[p. QADNLLMGK,SRHQADNLL,RHQADNLLM,HQADNLLMG, CRC 2 E69D]DNLLMGKEVGFFIIRASQSSPGD GLSRHQADNL,HQADNLLMGK,SRHQADNLLM FSI GRB1 c.898G>A p.A300 RHLQFFSEFGNSDIYVSLAGKKKHG[p.A KKHGTPTNY,HGTPTNYGF,TPTNYGFCF,GTPTNYGFCF,KK BRCA 4 T 300T]TPTNYGFCFKPNKAGGPRDLKML KHGTPTNY,KHGTPTNYGF CAE GRB7 c.716G>T p.R239 ISHEDLIQNFLNAGSFPEIQGFLQL[p.R2 LGSGRKLWK,EIQGFLQLL,LLGSGRKLW,LLGSGRKLWK,LQ LUAD L 39L]LGSGRKLWKRFFCFLRRSGLYYSTK LLGSGRKL,QLLGSGRKLW,PEIQGFLQLL G GREB c.1031C>A p.S344 ESPSAPDGGCPQGGGNRAKYESAGM[p. AGMYCVPQV,MYCVPQVGL,AKYESAGMY,YESAGMYCV, KIRC 1 Y S344Y]YCVPQVGLVGPASVTFPVVAS GMYCVPQVG,GMYCVPQVGL,KYESAGMYCV,MYCVPQV GEPVS GLV,RAKYESAGMY,YESAGMYCVP GRHL c.1822G>T p.G608 LVNMDDNIVKHYSNEDTFQLQIEEA[p. AWGSYKLTL,QIEEAWGSY,FQLQIEEAW,EEAWGSYKL,QIE LUAD 1 W G608W]WGSYKLTLTEI* EAWGSYK,TFQLQIEEAW,LQIEEAWGSY,IEEAWGSYKL,EE AWGSYKLT GRIA1 c.652C>T p.R218 EGYRMLFQDLEKKKERLVVVDCESE[p. CLNAILGQI,CESECLNAI,CLNQILGQII,CESECLNAIL CRC C R218C]CLNAILGQIIKLEKNGIGYHYILA NL GRIA2 c.2534G>A p.R845 LVGGLGLAMLVALIEFCYKSRAEAK[p.R KSRAEAKQM,AEAKQMKVA,KQMKVAKNA,KSRAEAKQM CRC Q 845Q]QMKVAKNAQNINPSSSQNSQN K,YKSRAEQKQM,KQMKVAKNAQ FATYK GRID1 c.1864G>A p.E622 PRPSASATLHSAIWIVYGAFVQQGG[p. GAFVQQGGK,KSSVNSMAM,VQQGGKSSV,GGKSSVNSM, DLBCL K E622K]KSSVNSMAMRIVMGSWWLFT FVQQGGKSSV,KSSVNSMAMR,GKSSVNSMAM LIVCSS GRID1 c.2048G>T p.R683 VSRMDNPIRTFQDLSKQVEMSYGTV[p. VLDSAVYEY,VEMSYGTVL,LDSAVYEYF,VLDSAVYEYF,TVL LUAD L R683L]LDSAVYEYFRAKGTNPLEQDSTF DSAVYEY,MSYGTVLDSA AEL GRID2 c.1947de|G p.T649f YTTLATRMMMGAWWLFALIVISSYT[p. SLLSSLLHA,LLSSLLHAL,TQTSLLSSL,LSSLLHALK,SLSRTFPS HNSC s T649fs]QTSLLSSLLHALKVPSSLSRTFP K,SSYTQTSLL,SSLSRTFPS,KQKSLMAQS,QTSLLSSLL,HALK SKQKSLMAQS* VPSSL,VPSSLSRTF,FPSKQKSLM,ISSYTQTSL,SLLSSLLHAL, VISSYTQTSL,YTQTSLLSSL,TQTSLLSSLL,LLSSLLHALK,ALKV PSSLSR,SSLSRTFPSK,KVPSSLSRTF,LSRTFPSKQK,RTFPSKQ KSL,FPSKQKSLMA,ISSYTQTSLL,LHALKVPSSL GRIK1 c.1103G>A p.R368 VSSLQCHRHKPWRLGPRFMNLIKEA[p. AQWDGLTGH,KEAQWDGLT,AQWDGLTGHI,LIKEAQWD LUAD Q R368Q]QWDGLTGHITFNKTNGLRKDF GL,FMNLIKEAQW,KEAQWDGLTG DLDII GRIN2 c.1556G>A p.R519 WNGMIGEVVMKRAYMAVGSLTINEE[p. TINEEQSEV,EEQSEVVDF,LTINEEQSEV,TINEEQSEVV,EQS OV B Q R519Q]QSEVVDFSVPFIETGISVMVS EVVDFSV,NEEQSEVVDF RSNGT GRK4 c.64_65ins p.K22fs MELENIVANSLLLKARQGGYGKK[p.K2 RQGGYGKKKW STAD A 2fs]KWS* GRM3 c.2046C>A p.F682 SALLTKTNCIARIFDGVKNGAQRPK[p.F KLISPSSQV,LISPSSQVF,LISPSSQVFI,KLISPSSQVF,AQRPKL HNSC L 682L]LISPSSQVFICLGLILVQIVMVSVW ISPS,VKNGAQRPKL L GRM3 c.547C>T p.R183 ANLLRLFQIPQISYASTSAKLSDKS[p.R1 LSDKSCYDY,KSCYDYFAR,AKLSDKSCY,LSDKSCYDYF,KLSD GBM C 83C]CYDYFARTVPPDFYQAKAMAEILR KSCYDY,SAKLSDKSCY FF GRM5 c.2685_268 p.P895f SSGETLRYKDRRLAQHKSEIECFTP[p.P8 WWESNNEQF,EIECFTPQR,SEIECFTPQ,REYGEWWES,EQ LUAD 6insC s 95fs]QREYGEWWESNNEQFQWKIRH FQWKIRH,FQWKIRHVG,TPQREYGEW,ESNNEQFQW,EW VGPE* WESNNEQF,EQFQWKIRHV,IECFTPQREY,WESNNEQFQ W,FQWKIRHVGP,REYGEWWESN,GEWWESNNEQ,TPQR EYGEWW GRM6 c.1089G>T p.E363 GFDQYFMTRSLENNRRNIWFAEFWE[p. WEDNFNCKL,EFWEDNFNCK,AEFWEDNFNC UCEC D E363D]DNFNCKLTSSGTQSDDSTRKCT GEER GRM6 c.2152_215 p.A718 SPTSQLVITFSLTSLQVVGMIAWLG[p.A MIAWLGGPA,GMIAWLGGPA KIRC 3insG fs 718fs]GPAPTQRD* GRM7 c.2036G>A p.R679 VCSFRRVFLGLGMCISYAALLTKTN[p.R ALLTKTNQI,LTKTNQIYR,KTNQIYRIF,LLTKTNQIY,QIYRIFE CRC Q 679Q]QIYRIFEQGKKSVTAPRLISPTSQL QGK,LTKTNQIYRI,KTNQIYRIFE,ALLTKTNQIY,LLTKTNQIY A R,TKTNQIYRIF GRM8 c.2554C>T p.R852 SVSLGMLYMPKVYIIIFHPEQNVQK[p.R VQKCKRSFK,KCKRSFKAV,CKRSFKAVV,NVQKCKRSFK,VQ LIHC C 852C]CKRSFKAVVTAATMQSKLIQKGN KCKRSFKA,KCKRSFKAVV DRP GTF2E c.575G>T p.R192 AMPKKDARTLLARFNEQIEPIYALL[p.R ALLLETEDV,IEPIYALLL,LETEDVNLA,LLLETEDVNL,LETEDV LUAD 1 L 192L]LETEDVNLAYEILEPEPTEIPALKQ NLAY,EPIYALLLET S GTF3A c.918G>T p.K306 HAGCGKTFAMKQSLTRHAVVHDPDK[p. VVFIDPDKNK,KNKMKLKVK,AVVHDPDKNK,KNKMKLKVK CRC N K306N]NKMKLKVKKSREKRSLASHLS K GYIPP GTF3C c.2299de|A p.S767f KEGPSGSGDSQLSASSRSESGRMKK[p. RMKKVIIKW,SGRMKKVII,RMKKVIIKWA,SGRMKKVIIK STAD 1 s S767fs]VIIKWA* GTF3C c.1685de|A p.E562f LIDLVRWKILKDKHIPQFLQEALEK[p.E5 AVESPIFGV,ALEKRLKAV,RLKAVESPI,SPIFGVLSF,LKAVESP STAD 4 s 62fs]RLKAVESPIFGVLSFSS* IF,VESPIFGVL,FLQEALEKRL,KAVESPIFGV,RLKAVESPIF,EA LEKRLKAV,KRLKAVESPI,VESPIFGVLS,QEALEKRLKA GUCY c.1645G>T p.G549 NFTEKQKIELNKLLQIDYYNLTKFY[p.G5 NLTKFYCTV,LTKFYCTVK,TKFYCTVKL,FYCTVKLDTM,LTKF BRCA 2C C 49C]CTVKLDTMIFGVIEYCERGSLREVL YCTVKL,YNLTKFYCTV,CTVKLDTMIF N GUSB c.1498T>C p.C500 PSRPVTFVSNSNYAADKGAPYVDVI[p.C RLNSYYSWY,IRLNSYYSW,VIRLNSYYS,DVIRLNSYY,APYVD KIRC R 500R]RLNSYYSWYHDYGHLELIQLQLA VIRL,VDVIRLNSY,YVDVIRLNSY,RLNSYYSWYH,DVIRLNSY TQF YS,VDVIRLNSYY,VIRLNSYYSW,IRLNSYYSWY GUSB c.1501T>G p.L501 SRPVTFVSNSNYAADKGAPYVDVIC[p.L CVNSYYSWY,DVICVNSYY,VDVICVNSY,ICVNSYYSW,APYV KIRC V 501V]VNSYYSWYHDYGHLELIQLQLAT DVICV,YVDVICVNSY,CVNSYYSWYH,DVICVNSYYS,VDVIC QFE VNSYY,CVNSYYSWY GXYLT c.667_668i p.L223f SQRLFLPLILKEVDSLLYVDTDILF[p.L22 YVDTDILFF,YVDTDILFFT,LYVDTDILFF STAD 1 nsT s 3fs]FTTS* H1FO c.642_643i p.A214 PGAATEKARKQGGAAKDTRAQSGEA[p.A2W APQARQGHA,ARQGHAGTF,GHAGTFQCW,HAGTFQCWW, BLCA O nsA fs 14fs]KEGAPQARQGHAGTFQCWW EAKEGAPQAR,QARQGHAGTF,GEAKEGAPQA,RQGHA AQQEGKGQRQQEQPRRC* GTFQC H2AF c.374A>G p.Q125 LIKATIAGGGVIPHIHKSLIGKKGQ[p.Q1 SLIGKKGQR,KSLIGKKGQR TGCT V R 25R]RKTA* H2AFV c.432de|G p.K144f GKSETILSPPPEKRGRKATSGKKGG[p.K GMDSPFCLL,RLPNHGRPK,LLRALFWDR,SPFCLLRAL,MGQ STAD 2 s 144fs]RNPRLPNHGRPKSPNQRTAIKKE GMDSPF,KKELQIPPL,KSPNQRTAIK,GMDSPFCLLR,KMGQ LQIPPLKMGQGMDSPFCLLRALFWDRS GMDSPF,SGKKGGRNPR,GGRNPRLPNH,HGRPKSPNQR,R CP* TAIKKELQI,CLLRALFWDR,RPKSPNQRTA,IPPLKMGQGM, SPFCLLRALF,NQRTAIKKEL,IKKELQIPPL,KELQIPPLKM,GQ GMDSPFCL H3F3C c.392G>T p.R131 DTNLCAIHAKRVTIMPKDIQLARRI[p.R LARRILGER,QLARRILGER,KDIQLARRIL LUAD L 131L]LGERA* HAO1 c.514C>T p.R172 AEKMGYKAIFVTVDTPYLGNRLDDV[p. RLDDVCNRF,RLDDVCNRFK CRC C R172C]CNRFKLPPQLRMKNFETSTLSFS PEE HAO2 c.34C>A p.H12N MSLVCLTDFQA[p.H12N]NAREQLSKS CLTDFQANA,FQANAREQL,QANAREQLSK,CLTDFQANAR LUAD TRDFIEGGADDSITRDD HARS c.503G>A p.R168 NKVKKMKRYHVGKVWRRESPTIVQG[p. IVQGHYREF,PTIVQGHYR,SPTIVQGHY,HYREFCQCDF,TIV CRC 2 H R168H]HYREFCQCDFDIAGQFDPMI QGHYREF,RESPTIVQGH PDAECL HAUS c.1588de|A p.S530f ENSPLSDVAKNTESSAFGGSLPAKK[p.S KVIHFKKSK,PAKKVIHFK,AKKVIHFKK,LPAKKVIHF,IHFKKS STAD 6 s 530fs]VIHFKKSKIIW* KII,SLPAKKVIHF,PAKKVIHFKK,KVIHFKKSKI,IHFKKSKIIW HBB c.126C>A p.F42L GKVNVDEVGGEALGRLLVVYPWTQR[p. VVYPWTQRL,RLFESFGDL,VYPWTQRLF,WTQRLFESF,RLF CRC F42L]LFESFGDLSTPDAVMGNPKVKA ESFGDLS,VVYPWTQRLF,PWTQRLFESF,LVVYPWTQRL,YP HGKK WTQRLFES HBB c.257T>G p.F86C VKAHGKKVLGAFSDGLAHLDNLKGT[p. NLKGTCATL,KGTCATLSEL KIRC F86C]CATLSELHCDKLHVDPENFRLLG NVL HCN1 c.1496G>T p.G499 PLFANADPNFVTAMLSKLRFEVFQP[p. VFQPVDYII,EVFQPVDYI,LRFEVFQPV,FEVFQPVDY,KLRFE LUSC V G499V]VDYIIREGAVGKKMYFIQHGVA VFQPV,RFEVFQPVDY,VFQPVDYIIR,EVFQPVDYII,FEVFQP GVIT VDYI HCN1 c.1976G>T p.R659 QAIAPINYPQMTTLNSTSSTTTPTS[p.R LMRTQSPPV,TTTPTSLMR,STTTPTSLM,SSTTTPTSL,SLMR LUSC L 659L]LMRTQSPPVYTATSLSHSNLHSPS TQSPPV,STTTPTSLMR,LMRTQSPPVY,SSTTTPTSLM PS HCN1 c.2140G>T p.A714 QPSAILSPCSYTTAVCSPPVQSPLA[p.A7 ASRTFHYAS,PLASRTFHY,LASRTFHYA,VQSPLASRT,PLASR LUSC S 14S]SRTFHYASPTASQLSLMQQQPQQ TFHYA,ASRTFHYASP,VQSPLASRTF,SPLASRTFHY QVQ HCN1 c.692C>A p.P231 IILDPKVIKMNYLKSWFVVDFISSI[p.P23 FISSIQVDY,QVDYIFLIV,IQVDYIFLI,SSIQVDYIF,VVDFISSIQ Q IQ]QVDYIFLIVEKGMDSEVYKTARALRI V,FISSIQVDYI,SIQVDYIFLI,IQVDYIFLIV,SSIQVDYIFL,ISSIQ LUAD VDYIF HCN1 c.976C>A p.P326 LIGMMLLLCHWDGCLQFLVPLLQDF[p. FTPDCWVSL,FLVPLLQDFT LUSC T P326T]TPDCWVSLNEMVNDSWGKQY SYALFK HCN4 c.1574G>A p.R525 IVGATCYAMFIGHATALIQSLDSSR[p.R SLDSSRHQY,SSRHQYQEK,RHQYQEKYK,IQSLDSSRH,SRH CRC H 525H]HQYQEKYKQVEQYMSFHKLPPD QYQEKY,QSLDSSRHQY,SSRHQYQEKY,HQYQEKYKQV TRQR HCRT c.26_27ins p.S9fs MSGTKLEDSPP[p.S9fs]LSQLVICFGAE DSPPLSQLV,SPPLSQLVI,TKLEDSPPL,LEDSPPLSQL STAD R2 C * HCRT c.26de|C p.S9fs MSGTKLEDSP[p.S9fs]LVATGHLLRS* LVATGHLLR,SPLVATGHL,LEDSPLVAT,GTKLEDSPLV,SPLV STAD R2 ATGHLL HCRT c.298G>T p.D100 VCVAVWKNHHMRTVTNYFIVNLSLA[p. FIVNLSLAY,IVNLSLAYV,NLSLAYVLV,SLAYVLVTI,YVLVTIT HNSC R2 Y D100Y]YVLVTITCLPATLVVDITETWFF CL,VNLSLAYVL,FIVNLSLAYV,SLAYVLVTIT,YFIVNLSLAY,AY GQS VLVTITCL,IVNLSLAYVL,LSLAYVLVTI HDAC c.2703de|C p.P901f PDEVGTGPGVGFNVNMAFTGGLDPP[p. GLDPPWETL,RMWCWCHQA,HQASMPWRA,ASLPRMW STAD 4 s P901fs]WETLSTWRPSERWSCRSPAS CW,RWSCRSPAS,RSPASLPRM,PWRATPPLL,LSTWRPSER, LPRMWCWCHQASMPWRATPPLLGAT RPSERWSCR,MPWRATPPL,WSCRSPASL,WCWCHQASM, TSPPDASGT* WCHQASMPW,FTGGLDPPW,PPWETLSTW,SPASLPRM W,RMWCWCHQAS,SMPWRATPPL,RWSCRSPASL,MWC WCHQASM,CWCHQASMPW,SCRSPASLPR,TLSTWRPSER, MPWRATPPLL,SERWSCRSPA,CRSPASLPRM,HQASMPW RAT,WETLSTWRPS,DPPWETLSTW HDAC c.3130G>A p.A104 CVSALLSVELQPLDEAVLQQKPNIN[p.A QQKPNINTV,NTVATLEKV,KPNINTVAT,LQQKPNINTV,NI CRC 5 4T 1044T]TVATLEKVIEIQSKHWSCVQKFA NTVATLEK,NTVATLEKVI,KPNINTVATL,QQKPNINTVA AGL HDLB c.1507C>T p.R503 SNLIRIEGDPQGVQQAKRELLELAS[p.R LASCMENER,RELLELASC,LELASCMEN,ELASCMENER,REL TGCT P C 503C]CMENERTKDLIIEQRFHRTIIGQK LELASCM GE HDLB c.2240de|G p.G747 EKQTKSFTVDIRAKPEYHKFLIGKG[p.G7 ALEHVSSSL,HVSSSLRLR,SSSLRLRTR,SLRLRTRTR,LIGKGA STAD P fs 47fs]AAKFARCATALEHVSSSLRLRTRTR AKF,AKFARCATA,KFARCATAL,FLIGKGAAKF,KFLIGKGAAK, T* KGAAKFARCA,AAKFARCATA,SSLRLRTRTR,VSSSLRLRTR, TALEHVSSSL,SLRLRTRTRT,FARCATALEH,HKFLIGKGAA,A KFARCATAL,LEHVSSSLRL HEAT c.3325G>A p.E110 TVVVNLLQKPLPFDRDTKTLWKALA[p. KTLWKALAK,TLWKALAKK,WKALAKKPA,KTLWKALAKK,L BLCA R7B2 9K E1109K]KKPASSGKLLQALIDKLETELED AKKPASSGK,AKKPASSGKL DIA HECA c.998_999i p.R333f MAGGHVFRNAHFDYSPAGLAVHRGG[p. AVHRGGTLR,RGGTLRHPR,GTLRHPRAV,RTPHSHPQA,HP STAD nsG s R333fs]TLRHPRAVPSAAGPLRTPHS RAVPSAA,LAVHRGGTL,GLAVHRGGTL,RGGTLRHPRA,LA HPQA* VHRGGTLR,HPRAVPSAAG,RAVPSAAGPL,LRHPRAVPSA,S AAGPLRTPH HECT c.55C>G p.P19A MSEAVRVPSPATPLVVAA[p.P19A]AA ATPLVVAAA,AAAAPEERK,TPLVVAAAA,VAAAAPEERK,AT ACC D2 PEERKGKESEREKLPPIVSAGAGA PLVVAAAA HECW c.547G>T p.A183 ICFKYYHGVSGALRATTPSVTVKNS[p.A KNSSAPIFK,TVKNSSAPI,SSAPIFKSI,VKNSSAPIF,VTVKNSS LUAD 1 S 183S]SAPIFKSIGADETVQGQGSRRLISF API,NSSAPIFKSI,TVKNSSAPIF S HERC c.6989G>A p.R233 PVLAVIGGVDAGLRVGGRCVHKQTG[p. HKQTGHHAT,KQTGHHATL,HKQTGHHATL,KQTGHHATLL GBM 1 0H R2330H]HHATLLGVVKEGSTSAKVQW DEAEIT HERC c.986C>T p.S329 SQMLSAILLLLQLWDSGAQETDNER[p. FAQGTSAPL,AQETDNERF,ERFAQGTSA,RFAQGTSAPL,GA CESC 2 F S329F]FAQGTSAPLLPLLQRFQSIICRKD QETDNERF,NERFAQGTSA,FAQGTSAPLL AP HES3 c.286C>A p.P96T SCLPGVSQLLRRGDEVGSGLRCPLV[p.P TESAAGSTM,CPLVTESAA,VTESAAGSTM ACC 96T]TESAAGSTMDSAGLGQEAPALFRP CT HEXD c.1444A>C p.T482 CRSWRLPCSWLSTRMPWRSGWRKTC[p. GWRKTCPPA KIRC,LUSC C P T482P]PPACSGCKLCCRTSARCLPPR CHPPA HGF c.1400C>A p.S467 NPDDDAHGPWCYTGNPLIPWDYCPI[p. IPWDYCPIY,LIPWDYCPIY,IPWDYCPIYR CRC Y S467Y]YRCEGDTTPTIVNLDHPVISCAK TKQ HGF c.2057T>C p.M68 AEKIGSGPCEGDYGGPLVCEQHKMR[p. KMRTVLGVI,EQHKMRTVL,HKMRTVLGV,CEQHKMRTV,K LUAD 6T M686T]TVLGVIVPGRGCAIPNRPGIFV MRTVLGVIV,VLGVIVPGR,CEQHKMRTVL,HKMRTVLGVI RVAY HGF c.686G>C p.G229 PQCSEVECMTCNGESYRGLMDHTES[p. GLMDHTESA,LMDHTESAK,LMDHTESAKI,GLMDHTESAK, CESC A G229A]AKICQRWDHQTPHRHKFLPER HTESAKICQR,TESAKICQRW YPDKG HHIPL c.2075T>C p.V692 AFRDGEVRLVRPAGLSSGSGRVEVF[p. VEVFAGGRW,EVFAGGRWGT ACC 1 A V692A]AGGRWGTVCDDSWNISGAAV VCRQLG HIF3A c.214G>A p.A72T VSAHLDKASIMRLTISYLRMHRLCA[p.A RMHRLCATG,LRMHRLCAT,HRLCATGEW,YLRMHRLCAT, CESC 72T]TGEWNQVGAGGEPLDACYLKALE MHRLCATGEW GFV HIP1 c.2819G>T p.R940 AQLVAASKVKADKDSPNLAQLQQAS[p. QLQQASLGV,LAQLQQASL,LQQASLGVN,AQLQQASLGV, LUAD L R940L]LGVNQATAGVVASTISGKSQIE NLAQLQQASL,QQASLGVNQA ETDN HIPK4 c.839G>A p.R280 PDAANPWQLKSSADYLAETKVRPLE[p. KVRPLEHRK,LEHRKYMLK,RPLEHRKYM,HRKYMLKSL,KVR CRC H R280H]HRKYMLKSLDQIETVNGGSVAS PLEHRKY,ETKVRPLEHR,RPLEHRKYML,EHRKYMLKSL RLTF HIST1 c.564G>C p.K188 AAAGVKKVAKSPKKAKAAAKPKKAT[p. ATNSPAKPK,KKATNSPAK,KATNSPAKPK,ATNSPAKPKA,K CESC H1B N K188N]NSPAKPKAVKPKAAKPKAAKPK PKKATNSPA AAKP HIST1 c.194C>T p.A65V VSELITKAVAASKERSGVSLAALKK[p.A6 ALKKVLAAA,VLAAAGYDV,AALKKVLAA,KKVLAAAGY,KVL DLBCL H1C 5V]VLAAAGYDVEKNNSRIKLGLKSLVSK AAAGYDV,SLAALKKVLA,LAALKKVLAA,LKKVLAAAGY HIST1 c.243C>G p.I81M SGVSLAALKKALMAGYDVEKNNSR[p.I RMKLGLKSL,NSRMKLGLK,MKLGLKSLV,RMKLGLKSLV,YD BLCA H1D 81M]MKLGLKSLVSKGTLVQTKGTGAS VEKNNSRM,SRMKLGLKSL GSF HIST1 c.398G>C p.G133 NKKAASGEAKPKAKKAGAAKAKKPA[p. AAAAKKPKK,AAKAKKPAA,AKKPAAAAK,KAKKPAAAAK,A DLBCL H1E A G133A]AAAKKPKKATGAATPKKSAKKT AKAKKPAAA,AKAKKPAAAA PKKA HIST1 c.74G>C p.R25P MSETAPAAPAAPAPAEKTPVKKKA[p.R KTPVKKKAPK,KAPKSAGAAK,KKAPKSAGAA LUAD H1E 25P]PKSAGAAKRKASGPPVSELITKAVA A HIST1 c.89G>C p.R30P GKQGGKARAKAKTRSSRAGLQFPVG[p. GLQFPVGPV,FPVGPVHRL,LQFPVGPVH,QFPVGPVHRL,F CESC H2AL R30P]PVHRLLRKGNYAERVGAGAPVY PVGPVHRLL LAAV HIST1 c.229G>A p.E77K DTGISSKAMGIMNSFVNDIFERIAG[p.E RIAGKASRL,GKASRLAHY,DIFERIAGK,RIAGKASRLA,KASR HNSC H2BF 77K]KASRLAHYNKRSTITSREIQTAVRLL LAHYNK,AGKASRLAHY,DIFERIAGKA HIST1 c.38A>G p.K13R MPEPAKSAPAPK[p.K13R]RGSKKAVTK RGSKKAVTK,APAPKRGSK,SAPAPKRGSK,APKRGSKKAV TGCT H2BJ AQKKDGKKRKRSRKESY HIST1 c.142G>T p.A48S TKAARKSAPATGGVKKPHRYRPGTV[p. RYRPGTVSL,SLREIRRYQ,VSLREIRRY,TVSLREIRR,HRYRPG DLBCL H3B A48S]SLREIRRYQKSTELLIRKLPFQRLV TVS,SLREIRRYQK,GTVSLREIRR,RYRPGTVSLR,TVSLREIRR R Y,RPGTVSLREI,HRYRPGTVSL HIST1 c.220G>A p.E74K LREIRRYQKSTELLIRKLPFQRLVR[p.E74 LVRKIAQDF,FQRLVRKIA,KLPFQRLVRK,LVRKIAQDFK,LPF LUSC H3B K]KIAQDFKTDLRFQSSAVMALQEACEA QRLVRKI,RLVRKIAQDF HIST1 c.110A>T p.K37 TGGKAPRKQLATKAARKSAPATGGV[p. GVMKPHRYR,VMKPHRYRP,KSAPATGGVM,VMKPHRYRP HNSC H3C M K37M]MKPHRYRPGTVALREIRRYQKS G TELL HIST1 c.203G>C p.R68P GVKRISGLIYEETRGVLKVFLENVI[p.R68 FLENVIPDA,VIPDAVTYT,NVIPDAVTY,LENVIPDAV,FLENV HNSC H4C P]PDAVTYTEHAKRKTVTAMDVVYALK IPDAV,NVIPDAVTYT,IPDAVTYTEH,LENVIPDAVT R HIST2 c.89G>C p.R30P GKQGGKARAKAKSRSSRAGLQFPVG[p. GLQFPVGPV,FPVGPVHRL,LQFPVGPVH,QFPVGPVHRL,F CESC H2AC R30P]PVHRLLRKGNYAERVGAGAPVY PVGPVHRLL MAAV HIST2 c.161G>A p.G54D KRKRSRKESYSIYVYKVLKQVHPDT[p.G KQVHPDTDI LUSC H2BE 54D]DISSKAMGIMNSFVNDIFERIAGE AS HIVEP c.1601de|C p.P534f LSSHSEKTKPEQSLLSLQHPPSTAP[p.P5 LQHPPSTAPL,HPPSTAPLCL STAD 3 s 34fs]LCLS* HIVEP c.1660de|C p.H554 PSTAPPVPLLRSHSMPSAACTISTP[p.H SMTISPTPK,STPTTPSEV,EVATPSMTI,TPSMTISPT,TPSEV STAD 3 fs 554fs]TTPSEVATPSMTISPTPKP* ATPS,SEVATPSMT,PSMTISPTPK,TPSEVATPSM,SEVATPS MTI HLA-A c.233A>G p.Q78R DDTQFVRFDSDAASQRMEPRAPWIE[p. WIEREGPEY,IEREGPEYW,PWIEREGPEY BLCA,PRAD Q78R]REGPEYWDQETRNVKAQSQTD RVDLG HLA-C c.312C>A p.N104 EGPEYWDRNTQIYKAQAQTDRESLR[p. QTDRESLRK,SLRKLRGYY,KLRGYYNQS,SLRKLRGYYN,KLR CESC K N104K]KLRGYYNQSEAGSHTLQSMYG GYYNQSE,RESLRKLRGY,ESLRKLRGYY CDVGP HLA- c.250G>A p.E84K LSEAYDEDQLFFFDFSQNTRVPRLP[p.E RLPKFADWA,NTRVPRLPK,RVPRLPKFA,TRVPRLPKF CRC DMA 84K]KFADWAQEQGDAPAILFDKEFCE WMI HLA- c.706_707i p.A236 YTAIAYWVPRNALPSDLLENVLCGV[p. HLLPEALLR,RGHCSHHLL,SHHLLPEAL,LENVLCGVGL,HHR LUAD DMA nsG fs A236fs]GLWPGCAGHHRGHCSHHLLP GHCSHHL,CSHHLLPEAL EALLR* HLA- c.340_341i p.G114 NSQKDILEEKRAVPDRMCRHNYELG[p. ELGEAHDPA,HNYELGEAH,RHNYELGEAH,YELGEAHDPA CESC DPB1 nsA fs G114fs]EAHDPAAPSPA* HLA- c.740G>A p.R247 AQSKMLSGIGGFVLGLIFLGLGLII[p.R2 LIIHHRGQK,GLIIHHRGQK PRAD DQB2 H 47H]HHRGQKGPRGPPPAGNISAMIQS GER HLA- c.748G>A p.G250 KMLSGIGGFVLGLIFLGLGLIIRHR[p.G2 LIIRHRSQK,RHRSQKGPR,GLIIRHRSQK PRAD DQB2 S 50S]SQKGPRGPPPAGNISAMIQSGERA QA HLCS c.1084G>A p.E362 LPPSSNIVQTPEDFNLLKSSNFRRY[p.E3 KSSNFRRYK,RYKVLREIL,SSNFRRYKV,NFRRYKVLR,SNFRR CRC K 62K]KVLREILTTLGLSCDMKQVPALTPL YKVL,RRYKVLREI,KVLREILTTL,KSSNFRRYKV,SSNFRRYKVL, Y SNFRRYKVLR,RYKVLREILT,FRRYKVLREI,RRYKVLREIL HLX c.34T>A p.S12T MFAAGLAPFYA[p.S12T]TNFSLWSAAY ATNFSLWSA,PFYATNFSL,FYATNFSLW,LAPFYATNF,TNFS HNSC CSSAGPGGCSFPLDPA LWSAA,GLAPFYATNF,PFYATNFSLW,ATNFSLWSAA,TNFS LWSAAY,YATNFSLWSA,APFYATNFSL HLX c.693C>G p.N231 GRPAGVHLSGLQPSAGQFFASLDPI[p. KEASAILSP,DPIKEASAI,QFFASLDPIK,KEASAILSPL,DPIKEA TGCT K N231K]KEASAILSPLNSNPRNSVQHQF SAIL QDTF HMCN c.398C>A p.S133 RELYVQGGGDCPEMSIGAIKIALEI[p.S1 YLPGSFIYV,IYLPGSFIY,AIKIALEIY,EIYLPGSFI,LEIYLPGSF,IK UCEC 1 Y 33Y]YLPGSFIYVFTDARSKDYRLTHEVL IALEIYL,YLPGSFIYVF,IYLPGSFIYV,AIKIALEIYL,GAIKIALEIY, Q EIYLPGSFIY,ALEIYLPGSF,LEIYLPGSFI HMG2 c.744G>C p.E248 EEFLNHSKAREAELRQLRKSNMEFE[p.E MEFEDRNAA,MEFEDRNAAL CRC 0A D 248D]DRNAALQKHVESMRTAVEKLEV DVIQ HNF1 c.1250C>T p.T417 GHNLLSPDGKMISVSGGGLPPVSTL[p.T GLPPVSTLM,STLMNIHSL,LMNIHSLSH,MNIHSLSHH,PPVS GBM B M 417M]MNIHSLSHHNPQQSQNLIMTPL TLMNI,LMNIHSLSH,LMNIHSLSHH,GGLPPVSTLM,LPPVS SGVM TLMNI HNF1 c.906C>G p.N302 GVSPSKAHGLGSNLVTEVRVYNWFA[p. RVYNWFAKR,VYNWFAKRR,FAKRRKEEA,AKRRKEEAF,RV KIRC B K N302K]KRRKEEAFRQKLAMDAYSSNQ YNWFAKRR,EVRVYNWFAK,WFAKRRKEEA,FAKRRKEEAF THSLN HOOK c.1083de|A p.L361f QVKTLQETNMMYMHNTVSLEEELKK[p. LEEELKKQM,LKKQMQHVH,EELKKQMQHV STAD 1 s L361fs]QMQHVHN* HOXA c.31G>T p.G11C MSSYFVNSFC[p.G11C]CRYPNGPDYQ FVNSFCCRY,CRYPNGPDY,YFVNSFCCR,YFVNSFCCRY,CCR LUAD 5 LHNYGDHSSVSEQFRD YPNGPDY,SYFVNSFCCR HOXD c.452A>G p.Y151 AEVPSYQRLVPESCPVENPEVPVPG[p.Y CFRLSQTYA,EVPVPGCFR,VPVPGCFRL,GCFRLSQTY,EVPV HNSC 10 C 151C]CFRLSQTYATGKTQEYNNSPEGS PGCFRL,NPEVPVPGCF STV HOXD c.201G>C p.Q67H GRHAAAAAALQLYGNSAAGFPHAPP[p. FPHAPPHAH,AGFPHAPPH,AGFPHAPPHA,FPHAPPHAHA KIRP 8 Q67H]HAHAHPHPSPPPSGTGCGGRE GRGQE HOXD c.364de|C p.P122f GSPAAAYQAAPPPPPHPPPPPPPPP[p. FTDTITYRD,RSFTDTITY,KRPSWYNIL,ITYRDSRFL,TYRDSR STAD 8 s P122fs]AAGLPVTGSPRSFTDTITYRDSR FLR,DSRFLRPSK,SFTDTITYR,DTITYRDSR,WYNILTVNR,NIL FLRPSKRPSWYNILTVNRPVVILARTQTT TVNRPV,TVNRPVVIL,SPRSFTDTI,RPSKRPSWY,SKRPSWY * NI,RSFTDTITYR,ITYRDSRFLR,RDSRFLRPSK,RFLRPSKRPS, VNRPVVILAR,DSRFLRPSKR,SWYNILTVNR,TVNRPVVILA,L PVTGSPRSF,SPRSFTDTIT,RPSWYNILTV,FLRPSKRPSW,SK RPSWYNIL,YNILTVNRPV HPD c.852_853d p.R284f GGAGVQHIALKTEDIITAIRHLRER[p.R2 GVLICSLHV,VLICSLHVL,SLHVLQTTA,VLQTTAGEA,HLRER UCEC e|AG s 84fs]PGVLICSLHVLQTTAGEAEDGQD PGVL,RPGVLICSL,RERPGVLIC,HLRERPGVLI,RHLRERPGVL, QGEGEH* RERPGVLICS HPS3 c.1403C>T p.S468L NHIILLTKAEPEAIPERRQSPKRLL[p.S46 LLLRKDTSV,LLRKDTSVK,RQSPKRLLL,RLLLRKDTSV,LLRKD CRC 8L]LRKDTSVKIKIPPVAEAGWNLYIVNT TSVKI,LLLRKDTSVK,RQSPKRLLLR,QSPKRLLLRK,RRSQPKR LLL HPS3 c.2436G>C p.K812 VACLPDVVLQELFFKLTSQYIWRLS[p.K QYIWRLSNR,SQYIWRLSN,SQYIWRLSNR,NRQPPDTTPL HNSC N 812N]NRQPPDTTPLRTSEDLINACSHY GLI HPSE2 c.174G>T p.K58N LHLSLSSQAGDRRPLPVDRAAGLKE[p.K GLKENTLIL,LKENTLILL,GLKENTLILL,RAAGLKENTL,KENTLI CRC 58N]NTLILLDVSTKNPVRTVNENFLSLQ LLDV L HRAS c.181C>A p.Q61K IEDSYRKQVVIDGETCLLDILDTAG[p.Q6 LDTAGKEEY,AGKEEYSAM,ILDTAGKEEY,DTAGKEEYSA THCA 1K]KEEYSAMRDQYMRTGEGFLCVFAI NN HRAS c.182A>G p.Q61R IEDSYRKQWIDGETCLLDILDTAG[p.Q6 LDTAGREEY,AGREEYSAM,ILDTAGREEY,AGREEYSAMR,D THCA 1R]REEYSAMRDQYMRTGEGFLCVFAI TAGREEYSA NN HRAS c.34G>A p.G12S MTEYKLVVVGA[p.G12S]SGVGKSALTI LVVVGASGV,KLVVVGASGV,YKLVVVGASG HNSC QLIQNHFVDEYDPTIE HRAS c.35G>A p.G12D MTEYKLVVVGA[p.G12D]DGVGKSALT LVVVGADGV,VVGADGVGK,KLVVVGADGV,VVVGADGVG BLCA,HNSC IQLIQNHFVDEYDPTIE K HRAS c.35G>C p.G12A MTEYKLVVVGA[p.G12A]AGVGKSALTI LVVVGAAGV,VVGAAGVGK,YKLVVVGAA,KLVVVGAAGV, HNSC QLIQNHFVDEYDPTIE VVVGAAGVGK,YKLVVVGAAG,GAAGVGKSAL HRAS c.38G>T p.G13V MTEYKLVVVGAG[p.G13V]VVGKSALTI KLVVVGAGV,VVGAGVVGK,KLVVVGAGVV,VVVGAGVVG HNSC QLIQNHFVDEYDPTIED K,YKLVVVGAGV HRC c.1317_131 p.P439f PHHHHHRVPREEDEEVSAELGHQAP[p. HQAPQPQAK,AELGHQAPQ KIRC 8insC s P439fs]QPQAKPPR* HRCT c.275A>C p.H92P LGIFHHHRHPGHVSHVPNVGLHHHH[p. GLHHHHPPR,PPRHTPHHL,VGLHHHHPPR,HPPRHTPHHL, BLCA 1 H92P]PPRHTPHHLHHHHHPHRHHPR HHHPPRHTPH HAR* HRNR c.1de|A p.M1fs [p.M1fs]CLNSYKASSLSSMFSTNMPPS NMPPSMGSM,SYKASSLSS,KASSLSSMF,MPPSMGSMI,LN OV MGSMIR* SYKASSL,YKASSLSSM,LSSMFSTNM,FSTNMPPSM,SMFST NMPP,SLSSMFSTNM,CLNSYKASSL,SMFSTNMPPS,NMP PSMGSMI,SYKASSLSSM,KASSLSSMFS,YKASSLSSMF,MFS TNMPPSM,NMPPSMGSM HRNR c.7615G>A p.G253 QHGSGSSQSSGYGRQGSGSGQSPGH[p. HSQRGSGSR CESC 9S p.G2539S]SQRGSGSRQSPSYGRHGSG SGRSSSS HRSP1 c.359G>A p.R120 IYKQYFKSNFPARAAYQVAALPKGS[p.R SQIEIEAVA,LPKGSQIEI,AALPKGSQI,SQIEIEAVAI,ALPKGS CRC 2 Q 120Q]QIEIEAVAIQGPLTTASL* QIEI HS3ST c.859G>A p.E287 RDRCLHESKGRAHPQVDPKLLNKLH[p. KLLNKLHKY,HKYFHEPNK,LLNKLHKYF,KLLNKLHKYF,KYFH CRC 1 K E287K]KYFHEPNKKFFELVGRTFDWH* EPNKKF,LHKYFHEPNK HS3ST c.1195G>T p.G399 EIDREVVRRLREFYRPFNLKFYQMT[p.G FYQMTWFIDF,NLKFYQMTW,LKFYQMTWFI,YQMTWFIDF LUAD 3A1 W 399W]WHDFGWDG* G,QMTWHDFGW,FNLKFYQMTW,KFYQMTWHDF,YQMT WHDFGW HSD1 c.937G>A p.G313 VPAKAEAGAEAGGGAGPGAEDEAGR[p. AEDEAGRSA,RSAVGDPEL,AEDEAGRSAV,GRSAVGDPEL ACC 7B1 S G313S]SAVGDPELGDPPAAPQ* HSD1 c.627C>G p.F209 EAFSDILRREIQHFGVKISIVEPGY[p.F20 YLRTGMTNM,SIVEPGYLR,YLRTGMTNMT,ISIVEPGYLR,G LUAD 7B6 L 9L]LRTGMTNMTQSLERMKQSWKEAP YLRTGMTNM,VEPGYLRTGM KHI HSF4 c.505C>T p.R169 QALRGVQESTEARLRELRQQNEILW[p. ILWWEVVTL,RQQNEILWW,LWWEVVTLR,NEILWWEVV, TGCT W R169W]WEVVTLRQSHGQQHRVIGKLI WEVVTLRQS,QQNEILWWEV,ILWWEVVTLR,EILWWEVV QCLFG TL,WEVVTLRQSH,NEILWWEVVT HSPA c.253G>T p.V85L DENGHISIPSMVSFTDNDVYVGYES[p. DVYVGYESL,YVGYESLELA,VYVGYESLEL LUAD 13 V85L]LELADSNPQNTIYDAKRFIGKIFTA E HSPA c.1447C>T p.R483 RIGSFTIQNVFPQSDGDSSKVKVKV[p.R KVKVKVCVN,KVKVCVNIH,VCVNIHGIF,CVNIHGIFSV,SSK UCEC 4L C 483C]CVNIHGIFSVASASVIEKQNLEGD VKVKVCV,KVKVKVCVNI,KVKVCVNIHG,VKVCVNIHGI,KV HS CVNIHGIF HSPB c.845G>T p.R282 HYVESIDPVTVSINSWIELEEDHLA[p.R2 HLALVEEAI,LEEDHLALV,ALVEEAITRM,IELEEDHLQL LUAD AP1 L 82L]LVEEAITRMLVCALKTAENPQNTR AW HTR2 c.656C>T p.S219 LKIIAVWTISVGISMPIPVFGLQDD[p.S2 LQDDLKVFK,GLQDDLKVF,PVFGLQDDLK,GLQDDLKVFK,I UCEC A L 19L]LKVFKEGSCLLADDNFVLIGSFVSFF PVFGLQDDL,FGLQDDLKVF,LKVFKEGSCL HTR3 c.706C>T p.R236 SVSSTYSILQSSAGGFAAIQFNVVM[p.R VVMCRHPLV,IQFNVVMCR,VMCRHPLVY,MCRHPLVYV,N CRC B C 236C]CRHPLVYVVSLLIPSIFLMLVDLGS VVMCRHPL,VMCRHPLVYV,VVMCRHPLVY,QIQFNVVMC F R,NVVMCRHPLV,AQIQFNVVMC,IQFNVVMCRH,FNVVM CRHPL HTR5 c.454C>T p.R152 ASIWNVTAIALDRYWSITRHMEYTL[p. CTRKCVSNV,HMEYTLCTR,YTLCTRKCV,RHMEYTLCT,HME CRC A C R152C]CTRKCVSNVMIALTWALSAVIS YTLCTRK,CTRKCVSNVM,MEYTLCTRKC LAPL HTR5 c.894G>T p.W29 DTWREQKEQRAALMVGILIGVFVLC[p. VLCCIPFFL,CIPFFLTEL,VFVLCCIPF,FVLCCIPFF,FVLCCIPFF LUAD A 8C W298C]CIPFFLTELISPLCSCDIPAIWKSI L,CIPFFLTELI,VFVLCCIPFF,GVFVLCCIPF F HTRA c.1208A>G p.Q403 DFPEVSSGIYVQEVAPNSPSQRGGI[p.Q GIRDGDIIVK GBM 3 R 403R]RDGDIIVKVNGRPLVDSSELQEA VLT HYAL4 c.664G>A p.D222 AFMKETIKLGIKSRPKGLWGYYLYP[p.D YLYPNCHNY,YPNCHNYNV,GLWGYYLYPN,YLYPNCHNYN, TGCT N 222N]NCHNYNVYAPNYSGSCPEDEVL YYLYPNCHNY,LYPNCHNYNV,YPNCHNYNVY RNNE HYDIN c.1352G>A p.R451 NPLEAKLYQQTIYCDILGREIRLPL[p.R45 EIRLPLQIK,REIRLPLQI,QIKGEGMGPK,LPLQIKGEGM CRC Q 1Q]QIKGEGMGPKIHFNFELLDIGKVFT G HYDIN c.2816G>A p.R939 PELNLGAHFSLDTHYYHFKLINKGR[p.R RQIQQLFWM,KLINKGRQI,KGRQIQQLF,KGRQIQQLFW,F CRC Q 939Q]QIQQLFWMNDSFRPQAKLSKKG KLINKGRQI,NKGRQIQQLF,RQIQQLFWMN RVKK HYDIN c.3559C>T p.R118 VHYPNLSFETKELDFGCILNDTELI[p.R1 LNDTELICY,TELICYVTI,ILNDTELICY,DTELICYVTI,TELI CRC 7C 187C]CYVTITNCSPLVVKFRWFFLVNDE CYVTIT EN HYOU c.472C>T p.R158 TVHFQISSQLQFSPEEVLGMVLNYS[p.R MVLNYSCSL,VLNYSCSLA,YSCSLAEDF,GMVLNYSCSL,MVL CRC 1 C 158C]CSLAEDFAEQPIKDAVITVPVFFN NYSCSLA,NYSCSLAEDF QA IARS2 c.2494C>T p.R832 YCEKENDPKRRSCQTALVEILDVIV[p.R8 VIVCSFAPI,CSFAPILPH,ILDVIVCSF,ILDVIVCSFA,VIVCSFA SKCM C 32C]CSFAPILPHLAEEVFQHIPYIKEPKS PIL,DVIVCSFAPI,EILDVIVCSF,CSFAPILPHL IBA57 c.390C>A p.S130 RTLYDVILYGLQEHSEVSGFLLECD[p.S1 FLLECDRSV,RSVQGALQK,LECDRSVQGA ACC R 30R]RSVQGALQKHLALYRIRRKVTVEP HP IBTK c.3638de|A p.K121 PVNAWASSLHSVSSKSFRDFLLEEK[p.K FLLEEKSLL,LLEEKSLLL,SLLLAIVQA,LLLAIVQAI,AIMSKKFLL, STAD 3fs 1213fs]SLLLAIVQAIMSKKFLLKELKILR FLLKELKIL,KLSDALPMV,LLAIVQAIM,AIVQAIMSK,IVQAI HQKLSDALPMVPQDQKATIFQIYHF* MSKK,IMSKKFLLK,KFLLKELKI,ATIFQIYHF,ELKILRHQK,LLK ELKILR,VPQDQKATI,VQAIMSKKF,SKKFLLKEL,LKILRHQKL, RHQKLSDAL,QKLSDALPM,QKATIFQIY,EEKSLLLAI,LEEKS LLLA,FLLEEKSLLL,SLLLAIVQAI,LLLAIVQAIM,LLEEKSLLLA, AIVQAIMSKK,AIMSKKFLLK,LAIVQAIMSK,IVQAIMSKKF,K ATIFQIYHF,KSLLLAIVQA,MSKKFLLKEL,DQKATIFQIY,VPQ DQKATIF,ELKILRHQKL,HQKLSDALPM,RDFLLEEKSL,LEEK SLLLAI,VQAIMSKKFL,KKFLLKELKI,LRHQKLSDAL,EEKSLLL AIV,LPMVPQDQKA IDE c.110de|A p.K37fs ALPSTFRSVLGARLPPPERLCGFQK[p.K GFQKRLTQK,CGFQKRLTQK STAD 37fs]RLTAK* IDH1 c.394C>G p.R132 VFREAIICKNIPRLVSGWVKPIIIG[p.R13 PIIIGGFIAY,GGHAYGDQY,KPIIIGGHAY,IGGHAYGDQY GBM G 2G]GHAYGDQYRATDFWPGPGKVEIT YT IDH1 c.394C>T p.R132 VFREAIICKNIPRLVSGWVKPIIIG[p.R13 PIIIGCHAY,GCHAYGDQY,KPIIIGCHAY,IGCHAYGDQY LAML,LIHC, C 2C]CHAYGDQYRATDFVVPGPGKVEITY MM,SKCM T IDH1 c.395G>A p.R132 VFREAIICKNIPRLVSGWVKPIIIG[p.R13 PIIIGHHAY,GHHAYGDQY,KPIIIGHHAY,IGHHAYGDQY GBM,LAML, H 2H]HHAYGDQYRATDFVVPGPGKVEIT PRAD YT IDH2 c.419G>A p.R140 TITPDEARVEEFKLKKMWKSPNGTI[p.R IQNILGGTV,QNILGGTVF,SPNGTIQNI,TIQNILGGTV,SPNG LAML Q 140Q]QNILGGTVFREPIICKNIPRLVPG TIQNIL,IQNILGGTVF WT IDH2 c.515G>A p.R172 VFREPIICKNIPRLVPGWTKPITIG[p.R17 WTKPITIGK,KHAHGDQYK,GKHAHGDQY,IGKHAHGDQY LAML K 2K]KHAHGDQYKATDFVADRAGTFKM VFT IDUA c.1120A>C p.T374 DNAFLSYHPHPFAQRTLTARFQVNN[p. NPRPPHVQL,FQVNNPRPP,TARFQVNNPR,QVNNPRPPH ACC P T374P]PRPPHVQLLRKPVLTAMGLLAL V,NPRPPHVQLL,FQVNNPRPPH LDEE IDUA c.99T>G p.H33Q AALLALLASLLAAPPVAPAEAPHLV[p.H HLVQVDAAR,VQVDAARAL,AEAPHLVQV,HLVQVDAARA, KIRP 33Q]QVDAARALWPLRRFWRSTGFCPP APHLVQVDAA,VQVDAARALW LPH IER5 c.580C>G p.R194 SRAARRPCGCPLGGEDPPGTPAATP[p. TPAATPGAA,TPAATPGAAC KIRP G R194G]GAACCCAPQPAEDEPPAPPAV CPRKR IFNA1 c.236T>C p.V79A KDRHDFRIPQEEFDGNQFQKAQAIS[p. ALHEMIQQT,AISALHEMI,KAQAISALH,QAISALHEM,QKA GBM,LUSC 0 V79A]ALHEMIQQTFNLFSTEDSSAAW QAISAL,FQKAQAISAL,QAISALHEMI,AQAISALHEM,ALHE EQSL MIQQTF IFNA1 c.238C>T p.L80F DRHDFRIPQEEFDGNQFQKAQAISV[p. KAQAISVFH,QAISVFHEM,QKAQAISVF,AQAISVFHEM,VF GBM 0 L80F]FHEMIQQTFNLFSTEDSSAAWEQ HEMIQQTF,QAISVFHEMI,FQKAQAISVF SLL IFT14 c.1990G>A p.E664 VDEGLKNYVPVNHFWDQSEPRLFVC[p. QSEPRLFVCK,EPRLFVCKAV,SEPRLFVCKA HNSC 0 K E664K]KAVQETPRSQPQSANGQPQD GRAGPA IFT17 c.2509G>A p.A837 YERAGDLFEKIHNPQKALECYRKGN[p. CYRKGNTFM,KGNTFMKAV,NTFMKAVEL,CYRKGNTFMK, STAD 2 T A837T]TFMKAVELARLAFPVEVVKLEE TFMKAVELAR,NTFMKAVELA,LECYRKGNTF,RKGNTFMK AWGD AV IFT17 c.2831C>T p.A944 AQHYASLQEYEIAEELYTKGDRTKD[p.A RTKDVIDMY,DVIDMYTQA,RTKDVIDMYT CRC 2 V 944V]VIDMYTQAGRWEQAHKLAMKC MRPED IGF2B c.556A>T p.T186 SSPSPPQRAQRGDHSSREQGHAPGG[p. SSQARQIDF,GSSQARQIDF CLL P2 S T186S]SSQARQIDFPLRILVPTQFVGAII GK IGF2R c.3942_394 p.T131 HKVAGLLTQKLTYENGLLKMNFTGG[p. KMNFTGGGH,MNFTGGGHL,KMNFTGGGHL,LKMNFTGG STAD 3insG 4fs T1314fs]GHLP* GH IGHM c.1843C>A p.R615 FLAEDRRINVAVTRARRHVAVICDS[p.R AVICDSSTV,STVNNHAFL,SSTVNNHAF,STVNNHAFLK,DSS LUAD BP2 S 615S]STVNNHAFLKTLVEYFTQHGEVR TVNNHAF TAF IGJ c.230G>A p.R77Q KCARITSRIIRSSEDPNEDIVERNI[p.R77 QIIVPLNNR,DIVERNIQI,VERNIQIIV,RNIQIIVPL CRC Q]QIIVPLNNRENISDPTSPLRTRFVYH IK c.268_269d p.E90fs DPAARRRKKKSYYAKLRQQEIERER[p.E EIERERASR,REVPGSCQG,TERWSEQRL,RQQEIERERA,IER UCEC e|GA 90fs]ASREVPGSCQGTERWSEQRL* ERASREV,REVPGSCQGT IKZF3 c.485T>G p.L162 KRSHTGERPFQCNQCGASFTQKGNL[p. KGNLRRHIK,SFTQKGNLR,FTQKGNLRR,ASFTQKGNLR,KG CLL R L162R]RRHIKLHTGEKPFKCHLCNYAC NLRRHIKL,SFTQKGNLRR,NLRRHIKLHT,TQKGNLRRHI QRRD IL17B c.100C>T p.R34 FLLTISIFLGLGQPRSPKSKRKGQG[p.R3 GQGWPGPLA,RKGQGWPGPL,WPGPLAPGPH BRCA W 4W]WPGPLAPGPHQVPLDLVSRMKPY ARM IL17R c.2409_241 p.Q803 PYEEEQRQSVQSDQGYISRSSPQPP[p. GLGHDGVRV,RAAPQGPPR,RGGRGAGPR,RVRGAQCMR, CRC A 0insC fs Q803fs]RGTHGNGGRGGRGAGPREA GPREAGPAT,VRVRGAQCM,EEPPAAAAF,REAGPATLS,ISR GPATLSRGPGEPEEPPAAAAFPPAAEEL SSPQPPR,GVRVRGAQCM,RVRGAQCMRA,GPREAGPATL, GLGHDGVRVRGAQCMRAAPQGPPRS APQGPPRSQL,AAFPPAAEEL,EELGLGHDGV QL* IL1R2 c.1091_109 p.L364f KEASSTFSWGIVLAPLSLAFLVLGG[p.L3 RLSILSQVK,QTVQTQNWK,KSRWSDCAM,MASSSRLSI,AQ CLL 2insG s 64fs]NMDAQTVQTQNWKSRWSDCA TVQTQNW,CAMASSSRL,ASSSRLSIL,SRLSILSQV,FLVLGG MASSSRLSILSQVK* NMDA,AMASSSRLSI,KSRWSDCAMA,SSRLSILSQV,TVQT QNWKSR,MASSSRLSIL,LAFLVLGGNM,VQTQNWKSRW, WKSRWSDCAM,DAQTVQTQNW IL1RA c.149T>G p.F50C DDWGLDTMRAIQVFEDEPARIKCPL[p. RIKCPLCEH,IKCPLCEHF,CEHFLKFNY,RIKCPLCEHF,CPLCE KIRC P F50C]CEHFLKFNYSTAHSAGLTLIWYW HFLKF,CEHFLKFNYS TRQ IL1RA c.1940C>T p.T647 KHEIPATTLPVPSLGNHHTYCNLPL[p.T MLLNGQLPL,YCNLPLML,HTYCNLPLM,LMLLNGQLPL,H CRC PL2 M 647M]MLLNGQLPLNNTLKDTQEFHRN TYCNLPLML,TYCNLPLMLL,LPLMLLNGQL,HHTYCNLPLM SSLL IL2 c.308G>T p.R103 CLEEELKPLEEVLNLAQSKNFHLRP[p.R1 RPMDLISNI,NFHLRPMDL,SKNFHLRPM,QSKNFHLRPM,K LUAD M 03M]MDLISNINVIVLELKGSETTFMCEY NFHLRPMDL,MDLISNINVI A IL25 c.502_503d p.C168f HGEKGTHKGYCLERRLYRVSLACVC[p.C AGGWSLFGK,SLFGKPGAR,GPAGGWSLF,HEGPGCPDA,SL KIRP e|TG s 168fs]AAPCDGLAGPAGGWSLFGKPG ACVCAAPC,RVSLACVCAA,WSLFGKPGAR,GPGCPDAWPL, ARCTTTCHEGPGCPDAWPL* LAGPAGGWSL,HEGPGCPDAW IL3 c.268G>A p.A90T DILMENNLRRPNLEAFNRAVKSLQN[p. TSAIESILK,KSLQNTSAI,NTSAIESIL,LQNTSAIESI,NTSAI CRC A90T]TSAIESILKNLLPCLPLATAAPTRH ESILK,AVKSLQNTSA,VKSLQNTSAI P IL32 c.643C>A p.P215 LWKQFQSFCCSLSELFMSSFQSYGA[p. SYGATRGDK,SFQSYGATR,SSFQSYGAT,FQSYGATRG,SSF LUAD T P215T]TRGDKEELTPQKCSEPQSSK* QSYGATR,QSYGATRGDK IL32 c.653_654i p.D218 QFQSFCCSLSELFMSSFQSYGAPRG[p.D APRGEQGGA SKCM nsG fs 218fs]EQGGADTPEVL* IL5RA c.139C>A p.L47I LLPDEKISLLPPVNFTIKVTGLAQV[p.L47 GLAQVILQW,GLAQVILQWK,IKVTGLAQVI,TGLAQVILQW CRC I]ILQWKPNPDQEQRNVNLEYQVKINA P IL6ST c.647C>A p.P216H FVNIEVWVEAENALGKVTSDHINFD[p. TSDHINFDH,HINFDHVYK,DHINFDHVY,TSDHINFDHV,HI MM P216H]HVYKVKPNPPHNLSVINSEELSS NFDHVYKV,SDHINFDHVY ILK IL7R c.161C>T p.S54L DLEDAELDDYSFSCYSQLEVNGSQH[p.S EVNGSQHLL,SQHLLTCAF,LEVNGSQHL,GSQHLLTCAF,LEV LUSC 54L]LLTCAFEDPDVNITNLEFEICGALVE NGSQHLL ILF3 c.1450G>A p.E484 VKVLQDMGLPTGAEGRDSSKGEDSA[p. SSKGEDSAK,KETEAKPAV,KETEAKPAVV,GEDSAKETEA BLCA K E484K]KETEAKPAVVAPAPVVEAVSTP SAAF INADL c.4018C>G p.P134 KLVFIRNEDAVNQMAVTPFPVPSSS[p. FPVPSSSAS,VPSSSASSI,TPFPVPSSSA,FPVPSSSASS LUSC 0A P1340A]ASSIEDQSGTEPISSEEDGSVE VGIK INF2 c.1581de|C p.S527f PLLPGMGWGPPPPPPPLLPCTCSPP[p. SWPRWTMAW,AWRRSSWPR,RSSWPRWTM,SSWPRWT STAD s S527fs]WREAWRRSSWPRWTMAWA MA,WPRWTMAWA,WAQHGSPAI,REAWRRSSW,WRRSS QHGSPAIGG* WPRW,AWAQHGSPA,AQHGSPAIG,LPCTCSPPW,AWRRS SWPRW,SSWPRWTMAW,RSSWPRWTMA,MAWAQHGS PA,CSPPWREAWR,EAWRRSSWPR,WTMAWAQHGS,WP RWTMAWAQ,LLPCTCSPPW,WREAWRRSSW,RRSSWPR WTM,AWAQHGSPAI ING1 c.658G>T p.A220 DECYERFSRETDGAQKRRMLHCVQR[p. MLHCVQRSL,RSLIRSQEL,RMLHCVQRS,RMLHCVQRSL,M LUAD S A220S]SLIRSQELGDEKIQIVSQMVELV LHCVQRSLI,RSLIRSQELG ENR INMT c.167G>T p.G56V PSPEAEMLKFNLECLHKTFGPGGLQ[p. LQVDTLIDI,GLQVDTLIDI,KTFGPGGLQV LUAD G56V]VDTLIDIGSGPTIYQVLAACDSFQ DI INMT c.635C>T p.S212 LKPGGHLVTTVTLRLPSYMVGKREF[p.S EFFCVALEK,YMVGKREFF,GKREFFCVA,KREFFCVAL,REFF SKCM F 212F]FCVALEKEEVEQAVLDAGFDIEQL CVAL,MVGKREFFCV,MVGKREFFC,SYMVGKREFF,GKR LH EFFCVAL,REFFCVALEK INPP5 c.1568G>A p.R523 SFMFNGTSLGFVNSHLTSGSEKKLR[p.R RQNQNYMNI,KLRQNQNYM,KKLRQNQNY,KLRQNQNYM CRC D Q 523Q]QNQNYMNILRFLALGDKKLSPF N,RQNQNYMNIL,KKLRQNQNYM NITH INPP5 c.787C>T p.R263 EGRLLFPPTYKFDRNSNDYDTSEKK[p.R KCKPAWTDR,SEKKCKPAW CRC K C 263C]CKPAWTDRILWRLKRQPCAGPD TPIP INPPL c.1478C>T p.T493 VFGTQENSVGDREWLDLLRGGLKEL[p. LMDLDYRPI,LKELMDLDY,ELMDLDYRPI,GLKELMDLDY,LL HNSC 1 M T493M]MDLDYRPIAMQSLWNIKVAVL RGGLKELM,MDLDYRPIAM VKPEH INPPL c.2921de|C p.A974 APREEPLTPRLKPEGAPEPEGVAAP[p.A RLPGPLSHL,SLGTTGTLV,YQGQWSGAV,ALSWGKWPV,VL STAD 1 fs 974fs]HPRTASITLPTTSLKGSRTSCCPRS QMRSLEA,GLRPVAHHL,HLPRPIQGL,ITLPTTSLK,LSHLPPR HPRLPGPLSHLPPRTKWPLQCLLHSLGT TK,TTGTLVWER,QTFHLHHCR,HQPALSWGK,MTGPARCC TGTLVWERGVLQMRSLEAHCPLQTFHL R,AWILYQGQW,SWGKWPVGM,RTASITLPT,GSRTSCCPR, HHCRTQPSSCPPAWILYQGQWSGAVV RTSCCPRSH,RSHPRLPGP,RTKWPLQCL,RSLEAHCPL,RPVA GLRPVAHHLPRPIQGLHCPQAPHQPAL HHLPR,PARCCRWPR,SCPPAWILY,EGVAAPHPR,SCCPRS SWGKWPVGMTGPARCCRWPRR* HPR,WSGAVVGLR,APHPRTASI,HPRTASITL,HPRLPGPLS,L PPRTKWPL,CPQAPHQPA,APHQPALSW,WPVGMTGPA,L QMRSLEAH,EAHCPLQTF,SHLPPRTKW,TKWPLQCLL,LLHS LGTTG,HSLGTTGTL,LGTTGTLVW,RGVLQMRSL,TQPSSCP PA,SSCPPAWIL,ILYQGQWSG,GQWSGAVVG,VAHHLPRPI, GLHCPQAPH,PQAPHQPAL,EPEGVAAPH,CPLQTFHLH,Q PSSCPPAW,QPALSWGKW,LEAHCPLQT,SSCPPAWILY,HL PPRTKWPL,ILYQGQWSGA,YQGQWSGAVV,GQWSGAVV GL,LLHSLGTTGT,SITLPTTSLK,TSCCPRSHPR,GTTGTLVWE R,RTASITLPTT,KGSRTSCCPR,RSHPRLPGPL,RTKWPLQCLL, RTQPSSCPPA,PARCCRWPRR,LQTFHLHHCR,QWSGAVV GLR,HSLGTTGTLV,APHPRTASIT,CPRSHPRLPG,HPRLPGP LSH,WPLQCLLHSL,CPQAPHQPAL,LEAHCPLQTF,LVWERG VLQM,ASITLPTTSL,LSHLPPRTKW,LHSLGTTGTL,SLGTTGT LVW,LQMRSLEAHC,MRSLEAHCPL,QPSSCPPAW,HQPA LSWGKW,LSWGKWPVGM,WERGVLQMRS,QPSSCPPAWI INPPL c.3460de|C p.P115 SEVDVAPAGPARSALLPGPLELQPP[p.P TMAGPSASL,SLHPASGRA,ASLHPASGR,RASRKTWQR,RT STAD 1 4fs 1154fs]GDCPRTMAGPSASLHPASGRA MAGPSAS,ASRKTWQRR,KTWQRRLRA,WQRRLRACR,RL SRKTWQRRLRACRAGGPAGWARQA* RACRAGG,RACRAGGPA,HPASGRASR,CPRTMAGPS,GPS ASLHPA,SGRASRKTW,RTMAGPSASL,RASRKTWQRR,ASR KTWQRRL,KTWQRRLRAC,RLRACRAGGP,ELQPPGDCPR,S ASLHPASGR,TWQRRLRACR,CPRTMAGPSA,WQRRLRAC RA,TMAGPSASLH,ASGRASRKTW INTS1 c.1A>G p.M1V [p.M1V]VAATVNLELDPIFLKALGFLHS VAATVNLEL MM 2 KSKD INTS4 c.1378T>G p.S460 MRKISNNITLREDQLDTVLAVLEDS[p.S VLAVLEDSA,SARDIREAL,SARDIREALH,DSARDIREAL TGCT A 460A]ARDIREALHELLCCTNVSTKEGIH LA INTS7 c.2818C>T p.R940 GIVWKTGPRTTIFVKSLEDPYSQQI[p.R DPYSQQICL,QQICLQQQQA UCEC C 940C]CLQQQQAQQPLQQQQQRNAY TRF* INTS7 c.317G>T p.R106I LCVLKVTQQSEKHLEKILNVDEFVK[p.R FVKIIFSVI,EFVKIIFSV,DEFVKIIFS,ILNVDEFVKI,EFVKIIFSVI, UCEC 106I]IIFSVIHSNDPVARAITLRMLGSLA DEFVKIIFSV S INVS c.2396G>A p.R799 WKPSRRHDTEPKAKCAPQKRRTQEL[p. PQKRRTQELK,ELKGGRCSPA CESC K R799K]KGGRCSPAGSSRPGSARGEAV HAGQN INVS c.2444de|G p.R815f KRRTQELRGGRCSPAGSSRPGSARG[p. SMLGRILPT,MLGRILPTI,SARGRRSML,RGRRSMLGR,RSM STAD s R815fs]RRSMLGRILPTIVHQETK* LGRILP,GSARGRRSM,RRSMLGRIL,SMLGRILPTI,MLGRILP TIV,ILPTIVHQET,SSRPGSARGR,SARGRRSMLG,RGRRSML GRI,RSMLGRILPT IPO11 c.2532de|T p.S844f ERYPVVMSTYLGVMGRVLLQNTSFF[p. LLQNTSFFL,YLMRWPINL,LMRWPINLI,TSFFLHYLM,SFFL STAD s S844fs]LHYLMRWPINLIRRWTSFWEI* HYLMR,FFLHYLMRW,RRWTSFWEI,LQNTSFFLH,QNTSFF LHY,NTSFFLHYL,LHYLMRWPI,NLIRRWTSF,LIRRWTSFW, WPINLIRRW,NTSFFLHYLM,VLLQNTSFFL,FLHYLMRWPI,Y LMRWPINLI,TSFFLHYLMR,SFFLHYLMRW,HYLMRWPINL, RWPINLIRRW,LMRWPINLIR,LQNTSFFLHY,INLIRRWTSF, NLIRRWTSFW,IRRWTSFWEI IRAK3 c.800G>A p.R267 PYMRNGTLFDRLQCVGDTAPLPWHI[p. IQIGILIGI,APLPWHIQI,WHIQIGILI,LPWHIQIGI,QIGILIGIS CRC Q R267Q]QIGILIGISKAIHYLHNVQPCSVI K,TAPLPWHIQI,LPWHIQIGIL CG IREB2 c.1256G>A p.R419 HLEHTGFSKAKLESMETYLKAVKLF[p.R FQNDQNSSG CRC Q 419Q]QNDQNSSGEPEYSQVIQINLNSI VPS IRF4 c.368A>G p.K123 RCALNKSNDFEELVERSQLDISDPY[p.K ISDPYRVYR,RVYRIVPEG,DISDPYRVY,DPYRVYRIV,QLDISD MM R 123R]RVYRIVPEGAKKGAKQLTLEDPQ PYRV,RVYRIVPEGA,SQLDISDPYR,DISDPYRVYR,LDISDPY MSM RVY IRS4 c.1771_177 p.G591 GHGSGGGQGPGDGHGSGGGKNSGG GQRLRKWER,RLRKWERIR,RLRKWERIRW,GKNSGGGQRL STAD 2insG fs G[p.G591fs]QRLRKWERIRW* IRS4 c.63_65de| p.21_2 MASCSFTRDQATRRLRGAAAAAAA[p. RGAAAAAAAL PAAD GGC 2AA>A 21_22AA>A]LAAVVTTPLLSSGTPTALI GTGSSCPGA IRX3 c.1265T>C p.L422 LVSAPLGKFPAWTNRPFPGPPPGPR[p. PPGPRPHPL,GPRPHPLSL,GPRPHPLSLL ACC P L422P]PHPLSLLGSAPPHLLGLPGAAGH PAA IRX6 c.1274C>T p.A425 CDESSCIPKAFGNPKFALQGLPLNC[p.A PLNCVPCPR,ALQGLPLNCV,VPCPRRSEPV STAD V 425V]VPCPRRSEPVVQCQYPSGAEAG* ISX c.256C>T p.R86C AASGSGLEKPPKDQPQEGRKSKRRV[p. KSKRRVCTT,CTTFTTEQL,SKRRVCTTF,RRVCTTFTT,KSKRR SKCM R86C]CTTFTTEQLHELEKIFHFTHYPDV VCTTF HI ISX c.5G>T p.C2F M[p.C2F]FAEVGPALCRGMERNSLGCC MFAEVGPAL LUSC EAPKKL ITGA1 c.2006G>A p.R669 PIVHLTPSLEVTPQAISWQRDCRR[p.R CRRQGQEAV,RQGQEAVCL,RRQGQEAVCL,RQGQEAVCL HNSC 0 Q 669Q]QGQEAVCLTAALCFQVTSRTPG T RWDH ITGA4 c.2018C>T p.T673 YLAVGSMKTLMLNVSLFNAGDDAYE[p. MTLHVKLPV,DAYEMTLHV,YEMTLHVKL,NAGDDAYEM,A CRC M T673M]MTLHVKLPVGLYFIKILELEEKQ YEMTLHVKL,DAYEMTLHVK,EMTLHVKLPV,FNAGDDAYE INC M,YEMTLHVKLP ITGA4 c.2700C>A p.F900 GIVRFLSKTDKRLLYCIKADPHCLN[p.F9 HCLNLLCNF,CLNLLCNFGK,IKADPHCLNL CRC L 00L]LLCNFGKMESGKEASVHIQLEGRP SI ITGA5 c.143C>A p.A48D PPLLPLLLLLLPPPPRVGGFNLDAE[p.A4 NLDAEDPAV KICH 8D]DPAVLSGPPGSFFGFSVEFYRPGTD G ITGA8 c.1846G>T p.G616 TEFRDKLSPINISLNYSLDESTFKE[p.G61 STFKECLEV,TFKECLEVK,KECLEVKPI,DESTFKECL,CLEVKPI LUAD C 6C]CLEVKPILNYYRENIVSEQAHILVDC LNY,STFKECLEVK,ESTFKECLEV,KECLEVKPIL ITGAX c.2054G>A p.R685 KRSKNLLGSRDLQSSVTLDLALDPG[p.R GHLSPRATF LUSC H 685H]HLSPRATFQETKNRSLSRVRVLGL KA ITGAX c.848G>A p.R283 TDGKKEGDSLDYKDVIPMADAAGII[p.R GIIHYAIGV,DAAGIIHYA,ADAAGIIHY,IHYAIGVGL,MADAA LUAD H 283H]HYAIGVGLAFQNRNSWKELNDI GIIHY,IIHYAIGVGL,HYAIGVGLAF,DAAGIIHYAI,IHYAIGVG ASKP LA ITGB1 c.1132C>A p.L378I PKSAVGTLSANSSNVIQLIIDAYNS[p.L3 LIIDAYNSI,QLIIDAYNSI,AYNSISSEVI,DAYNSISSEV STAD 78I]ISSEVILENGKLSEGVTISYKSYCKN ITGB1 c.472G>A p.D158 LKFKRAEDYPIDLYYLMDLSYSMKD[p.D SMKDNLENV,LSYSMKDNL,YSMKDNLENV,SMKDNLENV HNSC N 158N]NLENVKSLGTDLMNEMRRITSD K FRIG ITGB8 c.21_22insT p.A7fs MCGSALAFF[p.A7fs]YRCICLPAKRPAR CGSALAFFY,ALAFFYRCI,LVPLGSLGV,GSALAFFYR,FTCSWT STAD SRLVPLGSLGVFTCSWTGPR* GPR,FYRCICLPA,RSRLVPLGS,CLPAKRPAR,RPARSRLVP, VPLGSLGVF,PARSRLVPL,AKRPARSRL,SRLVPLGSL,SLGVF TCSW,RLVPLGSLGV,FFYRCICLPA,CGSALAFFYR,FYRCICLP AK,RSRLVPLGSL,MCGSALAFFY,VFTCSWTGPR,RPARSRL VPL,LAFFYRCICL,GSLGVFTCSW,SALAFFYRCI ITIH1 c.760G>T p.G254 KGHVLFRPTVSQQQSCPTCSTSLLN[p.G SLLNWHFKV,TSLLNWHFK,STSLLNWHF,LNWHFKVTY,ST LUAD W 254W]WHFKVTYDVSRDKICDLLVANN SLLNWHFK,CSTSLLNWHF,LLNWHFKVTY,TSLLNWHFKV HFAH ITIH2 c.2524C>G p.L842 TLDKEMSFSVLLHRVWKKHPVNVDF[p. VNVDFVGIY,NVDFVGIYI,HPVNVDFVG,VGIYIPPTNK,PVN LUAD V L842V]VGIYIPPTNKFSPKAHGLIGQFM VDFVGIY,HPVNVDFVGI QEP ITK c.586G>A p.E196 PEETVVIALYDYQTNDPQELALRRN[p.E LALRRNKEY,RRNKEYCLL,KEYCLLDSS,ALRRNKEYCL,ELAL CRC K 196K]KEYCLLDSSEIHWWRVQDRNGH RRNKEY EGYV ITK c.86G>T p.R29L FILLEEQLIKKSQQKRRTSPSNFKV[p.R2 SNFKVLFFV,VLFFVLTKA,KVLFFVLTK,NFKVLFFVL,SPSNFK LUAD 9L]LFFVLTKASLAYFEDRHGKKRTLKGS VLF,KVLFFVLTKA,TSPSNFKVLF,RTSPSNFKVL,SPSNFKVLF F,SNFKVLFFVL,LFFVLTKASL ITM2C c.499G>A p.E167 ADIIHDFQRGLTAYHDISLDKCYVI[p.E1 YVIKLNTTI,VIKLNTTIV,SLDKCYVIK,IKLNTTIVL,SLDKCYVIK UCEC K 67K]KLNTTIVLPPRNFWELLMNVKRGT L,YVIKLNTTIV,SLDKCYVIK,CYVIKLNTTI YL ITPR1 c.4707G>T p.M15 CGLERDKFDNKTVTFEEHIKEEHNM[p. NMCHYLCFI,HNMCHYLCF,KEEHNMCHY,CHYLCFIVL,EEH TGCT 69I M1569I]CHYLCFIVLVKVKDSTEYTGPE NMCHYL,NMCHYLCFIV,HNMCHYLCFI,IKEEHNMCHY,KE SYVA EHNMCHYL,MCHYLCFIVL ITPR2 c.1073C>A p.P358 RDGVPPTSKKKRQAGEKIMYTLVSV[p. IMYTLVSVQ,VQHGNDIAS,IMYTLVSVQH,VQHGNDIASL, LUAD Q P358Q]QHGNDIASLFELDATTLQRADC QHGNDIASLF LVPR IWS1 c.2404de|A p.S802f FQATSKKGISRLDKQMRKFTDIRKK[p.S RKFTDIRKKA STAD s 802fs]ADLHTQ* JAG1 c.1384G>A p.A462 DCLPGWMGQNCDININDCLGQCQND TSCRDLVNGY,CQNDTSCRDL CRC T [p.A462T]TSCRDLVNGYRCICPPGYAG DHCERD JAK1 c.928G>A p.V310I IFETSMLLISSENEMNWFHSNDGGN[p. SNDGGNILY,NILYYEVMV,ILYYEVMVT,HSNDGGNIL,GNIL CRC V310I]ILYYEVMVTGNLGIQWRHKPNV YYEVM,HSNDGGNILY,SNDGGNILYY,FHSNDGGNIL VSVE JAKMI c.848G>T p.R283I MSSPKREIPGRAGDGSEHCSSPDLR[p. INQKRIAEL,RINQKRIAEL,SSPDLRINQK UCEC P2 R283I]INQKRIAELNATIRKLEDRNTLLG DE JARID c.1180_118 p.G394 VNHTISGKTESSNAKTRKQVLSLGG[p. GQWQVEPKV,QWPQGQWQV,GVQVHWARR,RQWPQGQWQ, STAD 2 1insG fs G394fs]GVQVHWARRQWPQGQWQVE WQVEPKVMH,VLSLGGGVQV,RQWPQGQWQV, PKVMH* KQVLSLGGGV,LSLGGGVQVH,SLGGGVQVHW,VQVHWAR RQW,ARRQWPQGQW,GQWQVEPKVM JARID c.1266de|G p.V422 TGPAVNGLKVSGRLNPKSCTKEVGG[p. CGRACSCGR,KRHTRRRSR,HTRRRSRSR,RRSRSRPPR,RSRS STAD 2 fs V422fs]GSCGRACSCGRGCGTPRGDW RPPRR,EVGGGSCGR,HTRRRSRSRP,RRRSRSRPPR KRHTRRRSRSRPPRR* JHDM c.289de|A p.R97fs HHAVDIDLYHCPNCAVLHGSSLMKK[p. MMVPNQCKL,MTTQKLMMV,LMMVPNQCK,VPNQCKLE STAD ID R97fs]GGTGTDMTTQKLMMVPNQCK L,ELSLRNYAL,KKGGTGTDM,TDMTTQKLM,NQCKLELEL,C LELELSLRNYALESSQVPMK* KLELELSL,ALESSQVPM,LELSLRNYA,GTDMTTQKLM,LM MVPNQCKL,SLMKKGGTGT,KLMMVPNQCK,ALESSQVPM K,GTGTDMTTQK,YALESSQVPM,MKKGGTGTDM,TDMTT QKLMM,LELELSLRNY,LELSLRNYAL,RNYALESSQV JHDM c.938G>A p.R313 TSVWYHVLWGEKIFYLIKPTDENLA[p.R PTDENLQHY,AHYESWSSS,DENLQHYES,KPTDENLAHY,AH GBM 1D H 313H]HYESWSSSVTQSEVFFGDKVDKC YESWSSSV,DENLAHYESW YKC JMJD1 c.3592C>A p.R119 SHSVTTFRNDCRSPTHLTVSSTNTL[p.R LSSMPALHR,SSMPALHRA,NTLSSMPAL,SSTNTLSSM,TLS LUAD C 8S 1198S]SSMPALHRAPVFHPPIHHSLERK SMPALHR,STNTLSSMPA,VSSTNTLSSM EGS JMJD4 c.32C>T p.A11V MRAGPEPQAL[p.A11V]VGQKRGALRL LVGQKRGAL,LVGQKRGALR ACC LVPRLVLTVSAPAEVR JMY c.2429_246 p.PPPP LNNNLEPCSVTINPLPSPLPPTPPP[p.PP SPLPPTPPPL,LPPTPPPLPV PAAD 4de|CACCA PPPPPP PPPPPPPPPP811de|]LPVAKDSGPETLE CCACCTCCC PP811d KDLPRKEGNEKRIPKSASAPSAHLFDSS CCACCTCCT e| QLVSARKKLRKTAEGLQRRR CCCCCTCCC CCAC JPH1 c.1183G>A p.A395 ARTKVEIANSRTAHARAKADAADQA[p. DAADQATLA,TLAARQECDI,DAADQATLAA,KADAADQAT GBM T A395T]TLAARQECDIARAVARELSPDFY L QPG JPH3 c.1299G>C p.Q433 EARIARITAKEFSPSFQHRENGLEY[p.Q4 NGLEYHRPKR,YHRPKRQTSC CESC H 33H]HRPKRQTSCDDIEVLSTGTPLQQE SP JSRP1 c.275T>C p.V92A EKEPAARGTPGTGKERLKAGASPRS[p. KAGASPRSA,SPRSAPARK,RSAPARKKA,ASPRSAPARK/GA KIRP V92A]APARKKAQTAPPLQPPPPPPALS SPRSAPAR,APARKKAQTA,LKAGASPRSA EEL JUP c.1880C>T p.S627 RVAAGVLCELAQDKEAADAIDAEGA[p. ALAPLMELL,AEGALAPLM,GALAPLMEL,DAIDAEGAL,DAI CESC L S627L]LAPLMELLHSRNEGTATYAAAV DAEGALA,DAEGALAPL LFRI KAL1 c.907G>A p.V303I SKHFRSSKDPSAPPAPANLRLANST[p.V STINSDGSV,NLRLANSTI,TINSDGSVTV,NSTINSDGSV,ANL CRC 303I]INSDGSVTVTIVWDLPEEPDIPVH RLANSTI HY KANK c.1076G>A p.R359 VEADAWVTEALLGLPAAAERELELL[p.R AERELELLH,RELELLHAS,LLHASLEHQR,AERELELLHA,RELE ACC 3 H 359H]HASLEHQRGVSELLRGRLRELEE LLHASL,LELLHASLEH ARE KANK c.757T>C p.S253 VQEGAEPPEGVVKVPNHLPLPGPPF[p. PLPGPPFPF,PFQNVLVVL,FPFQNVLVV,GPPFPFQNV,LPLP KIRC 4 P S253P]PFQNVLVVLEDKEDEHNAREAE GPPFPF,GPPFPFQNVL,FPFQNVLVVL,PPFPFQNVLV VLFT KANSL c.1127G>A p.G376 IGWNTGALVACHVSVMEYVTAVVCL[p. AVVCLEFPL,CLEFPLLTV,VTAVVCLEF,LEFPLLTVD,YVTAVV TGCT 3 E G376E]EPLLTVDGPRGDVDDPLLDM CLEF,TAVVCLEFPL KTPVL KBTB c.242C>T p.A81V GGFRATLQVLRGDRPALAAEDELLQ[p. QVVECAAFL,LQVVECAAF,AEDELLQVV,LLQVVECAAF,LQ ACC D13 A81V]VVECAAFLQAPALARFLEHNLTS VVECAAFL,DELLQVVECA DNC KBTB c.1325_132 p.G442 LADRLLCREGMDVAYLNGYIYILGG[p.G YILGGARPY,ILGGARPYY,YIYILGGAR,ILGGARPYYW,IYILG STAD D6 6insG fs 442fs]ARPYYWS* GARPY,YILGGARPYY,GYIYILGGAR KBTB c.1645G>A p.V549I YLKLVLFQNKLHLFVRATQVTVEEH[p.V VTVEEHIFR,TQVTVEEHI,IFRTSRKNSL,QVTVEEHIFR,TQVT CRC D8 549I]IFRTSRKNSLYQYDDIADQWMKV VEEHIF YET KCNA c.1126G>T p.G376 EAESHFSSIPDAFWWAVVSMTTVGY[p. TTVGYCDMY,VGYCDMYPV,MTTVGYCDMY,TVGYCDMY LUAD 1 C G376C]CDMYPVTIGGKIVGSLCAIAGV PV,GYCDMYPVTI,SMTTVGYCDM LTIA KCNA c.1244C>T p.A415 TLKASMRELGLLIFFLFIGVILFSS[p.A41 ILFSSVVYF,GVILFSSVV,VILFSSVVY,SSVVYFAEA,FIGVILFS CRC 3 V 5V]VVYFAEADDPTSGFSSIPDAFWWA SV,ILFSSVVYFA,FSSVVYFAEA,VILFSSVVYF,GVILFSSVVY VV KCNB c.692G>A p.R231 STIALSLNTLPELQETDEFGQLNDN[p.R HQLAHVEAV,QLNDNHQLA,GQLNDNHQL,GQLNDNHQL BRCA 2 H 231H]HQLAHVEAVCIAWFTMEYLLRFL A,HQLAHVEAVC,DEFGQLNDNH SSP KCNC c.1363de|A p.K455f VPVIVNNFGMYYSLAMAKQKLPKKK[p. KQKLPKKKR,RSWDLPIIV,LPKKKRSIF,SIFRGFIRSW,GHRS STAD 1 s K455fs]RSIFRGHRSWDLPIIVNLS* WDLPI,WDLPIIVNL,IFRGHRSWDL,KKRSIFRGHR,RGHRS WDLPI,LPKKKRSIFR,RSIFRGHRSW,GHRSWDLPII KCND c.1313C>T p.S438 NQRADKRRAQKKARLARIRVAKTGS[p.S4 SLNAYLHSK,KTGSLNAYL,LNAYLHSKR,IRVAKTGSL,AKTGS CRC,UCEC 3 L 38L]LNAYLHSKRNGLLNEALELTGTP LNAY,GSLNAYLHSK,KTGSLNAYLH,SLNAYLHSKR,RIRVAK EEE TGSL,RVAKTGSLNA,VAKTGSLNAY,AKTGSLNAYL KCNH c.446G>C p.G149 MFILNFEVVMEKDMVGSPAHDTNHR[p. RAPPTSWLA,NHRAPPTSW,HRAPPTSWL STAD 2 A G149A]APPTSWLAPGRAKTFRLKLP ALLALT KCNH c.1365G>A p.M45 SSLTSVGFGNVSANTDAEKIFSICT[p.M KIFSICTIL,ILIGALMHA,SICTILIGA,IFSICTILI,CTILIGALM,EK LUAD 8 5I 455I]ILIGALMHALVFGNVTAIIQRMYS IFSICTI,KIFSICTILI,FSICTILIGA,ILIGALMHAL,SICTILIGAL, RW AEKIFSICTI,EKIFSICTIL KCNJ1 c.305de|C p.P102f GTWFLFGVVWYLVAVAHGDLLELDP[p. LAMASATSV,SMQLWPPTM,MQLWPPTMA,SLEPSSSPL, STAD 0 s P102fs]RPTTPPVWYRCTHSLEPSSSPL NVHWPLCFL,RLPGPRSGL,AMASATSVR,SSSQVPSWR,SS NPKPPLAMASATSVRNVHWPLCFLLPS QVPSWRR,VWYRCTHSL,RNVHWPLCF,VHWPLCFLL,SVR WCSPPSWKSSSQVPSWRRLPGPRSGL NVHWPL,SWCSPPSWK,SWRRLPGPR,SGLRPFVSA,PTTPP RPFVSASMQLWPPTMASPAS* VWYR,DPRPTTPPV,SPLNPKPPL,KPPLAMASA,VPSWRRLP G,GPRSGLRPF,WPPTMASPA,FLLPSWCSP,KSSSQVPSW,S QVPSWRRL,LRPFVSASM,FVSASMQLW,ASMQLWPPT,W PLCFLLPS,LPSWCSPPS,LELDPRPTT,FLLPSWCSPP,SMQL WPPTMA,PLAMASATSV,LLPSWCSPPS,GLRPFVSASM,LA MASATSVR,PSWCSPPSWK,KSSSQVPSWR,SSSQVPSWRR, PFVSASMALW,HSLEPSSSPL,SVRNVHWPLC,SWKSSSQV PS,SWRRLPGPRS,RSGLRPFVSA,ASMQLWPPTM,RPTTPP VWYR,MASATSVRNV,TSVRNVHWPL,NVHWPLCFLL,GPR SGLRPFV,RPFVSASMQL,SATSVRNVHW,VRNVHWPLCF,R NVHWPLCFL,WKSSSQVPSW,SQVPSWRRLP,RRLPGPRSG L,MQLWPPTMAS,WPLCFLLPSW,LPSWCSPPSW,DPRPTT PPVW KCNJ3 c.1290G>T p.L430 KITGRED[pKKLLRMSSTTSEKAYS[p.L4 YSFGDLPMK,AYSFGDLPM,SFGDLPMKL,TTSEKAYSF,KAY LUAD F 30F]FGDLPMKLQRISSVPGNSEEKLVSK SFGDLPM,AYSFGDLPMK,YSFGDLPMKL,STTSEKAYSF,SEK T AYSFGDL KCNK c.61A>G p.S21G MYRPRARAAPEGRVRGCAVP[p.S21G] GTVLLLLAY,RVRGCAVPG,CAVPGTVLL,VPGTVLLLL,RVRG ACC 17 GTVLLLLAYLAYLALGTGVFWTLEGR CAVPGT,PGTVLLLLAY,RGCAVPGTVL,CAVPGTVLLL,VPGT VLLLLA KCNK c.68G>T p.G23V MEVSGHPQARRCCPEALGKLFP[p.G23 ALGKLFPVL,KLFPVLCFL,VLCFLCFLV,EALGKLFPV,GKLFPV LUAD 18 V]VLCFLCFLVTYALVGAVVFSAIEDGQ LCF,FPVLCFLCF,KLFPVLCFLC,LFPVLCFLCF,FPVLCFLCFL,L GKLFPVLCF,GKLFPVLCFL,PEALGKLFPV KCNK c.17C>G p.S6W MLPSA[p.S6W]WRERPGYRAGVAAPD AWRERPGYR,SAWRERPGY,MLPSAWRER,SAWRERPGYR, BLCA 2 LLDPKSAAQNS AWRERPGYRA,PSAWRERPGY KCNK c.497G>T p.R166 HWDLGSSFFFAGTVITTIGFGNISP[p.R1 IGFGNISPL,SPLTEGGKIF LUAD 2 L 66L]LTEGGKIFCIIYALLGIPLFGFLLAG KCNM c.453T>G p.N151 KLLLYHTEETIKINQKCSYIPKCGK[p.N15 CGKKFEESM,KKFEESMSL,CSYIPKCGKK,SYIPKCGKKF,KKF STAD B2 K 1K]KFEESMSLVNVVMENFRKYQHFSC EESMSLV YS KCNS2 c.631G>A p.D211 SRVFSILSILVVMGSIITMCLNSLP[p.D21 MCLNSLPNF,CLNSLPNFQI,TMCLNSLPNF UCEC N 1N]NFQIPDSQGNPGEDPRFEIVEHFGI A KCTD2 c.942de|A p.L314f KLYRFFKYIENRDVAKTVLKERGLK[p.L3 KTFALELKV,RVAMWISSV,GLKTFALEL,KLREGLAAG,KVTL CRC 0 s 14fs]TFALELKVTLPVKKKLREGLAAGLK PVKKK,IMYNAPSSR,SVFEANPSR,VAMWISSVF,ELKVTLPV SSIIMYNAPSSRCHGKRKKGRVAMWIS K,KSSIIMYNA,SSRCHGKRK,KRKKGRVAM,KGRVAMWIS, SVFEANPSRIW* GLKSSIIMY,LKERGLKTF,FALELKVTL,LELKVTLPV,KKLREGL AA,LAAGLKSS,AGLKSSIIM,RKKGRVAMW,MWISSVFEA,F EANPSRIW,KERGLKTFA,ALELKVTLPV,KLREGLAAGL,GLA AGLKSSI,AMWISSVFEA,IMYNAPSSRC,SVFEANPSRI,GLKT FALELK,IIMYNAPSSR,TFALELKVTL,RVAMWISSVF,VFEAN PSRIW,RGLKTFALEL,SSRCHGKRKK,KGRVAMWISS,AGLK SSIIMY,VTLPVKKKLR,VLKERGLKTF,KERGLKTFAL,LAAGLK SSII,AAGLKSSIIM,GKRKKGRVAM,RKKGRVAMWI,GRVA MWISSV,REGLAAGLKS KCTD2 c.17C>T p.T6M MSDPI[p.T6M]MLNVGGKLYTTSLATLT MSDPIMLNV,MLNVGGKLY,IMLNVGGKL,IMLNVGGKLY STAD 1 SFPDSMLGA KDELC c.1339C>A p.L447I LKWAKDHDEEAKKIAKAGQEFARNN[p. IMGDDIFCY,GQEFARNNI,QEFARNNIM,IMGDDIFCYY,NI CRC 1 L447I]IMGDDIFCYYFKLFQEYANLQVS MGDDIFCY,GQEFARNNIM,RNNIMGDDIF EPQ KDM1 c.1083C>A p.F361 HLSNLEYACGSNLHQVSARSWDHNE[p. RSWDHNELF,ARSWDHNEL,DHNELFAQF,NELFAQFAG,S UCEC B L F361L]LFAQFAGDHTLLTPGYSVIIEKL ARSWDHNEL,RSWDHNELFA,ARSWDHNELF,WDHNELFA AEG QF KDM3 c.3946de|C p.P131 SLRDLLHSGPGKLPQTPLDTGIPFP[p.P1 FPRSSLHPQ,IPFPRSSLH,TGIPFPRSSL STAD B 6fs 316fs]RSSLHPQQE* KDM5 c.1267C>T p.P423 VSSIEEDVIVEYGADISSKDFGSGF[p.P4 SVKDGRRKI,DFGSGFSVK,KDFGSGFSV,SSKDFGSGFS,KDF TGCT A S 23S]SVKDGRRKILPEEEEYALSGWNLN GSGFSVK,SVKDGRRKIL NM KEAP1 c.1408C>T p.R470 PERDEWHLVAPMLTRRIGVGVAVLN[p. VAVLNCLLY,AVLNCLLYA,VLNCLLYAV,CLLYAVGGF,GVAV LUSC C R470C]CLLYAVGGFDGTNRLNSAECYY LNCLLY,AVLNCLLYAV PERN KEAP1 c.1438G>T p.G480 PMLTRRIGVGVAVLNRLLYAVGGFD[p. LYAVGGFDW,AVGGFDWTNR,LLYAVGGFDW,FDWTNRL LUSC W G480W]WTNRLNSAECYYPERNEWR NSA MITAMNT KEAP1 c.1807G>T p.G603 LDSVECYDPDTDTWSEVTRMTSGRS[p. RMTSGRSWV,SWVGVAVTM,SGRSWVGVA,TRMTSGRS LUAD W G603W]WVGVAVTMEPCRKQIDQQN W,GRSWVGVAV,RSWVGVAVT,MTSGRSWVGV,SGRSWV CTC* GVAV,RSWVGVAVTM,VTRMTSGRSW,RMTSGRSWVG KEAP1 c.431C>T p.S144 GMEVVSIEGIHPKVMERLIEFAYTA[p.S FISMGEKCV,TAFISMGEK,FAYTAFISM,YTAFISMGE,LIEFA LUAD F 144F]FISMGEKCVLHVMNGAVMYQID YTAF,IEFAYTAFI,RLIEFAYTAF,LIEFAYTAFI,FISMGEKCVL,Y SVVR TAFISMGEK,IEFAYTAFIS,EFAYTAFISM KEAP1 c.463G>T p.V155 PKVMERLIEFAYTASISMGEKCVLH[p.V VLHFMNGAV,FMNGAVMYQ,HFMNGAVMY,CVLHFMN LUSC F 155F]FMNGAVMYQIDSVVRACSDFLV GA,MGEKCVLHF,GEKCVLHFM,LHFMNGAVM,CVLHFMN QQLD GAV,FMNGAVMYQI,SMGEKCVLHF,LHFMNGAVMY,VLH FMNGAVM KEAP1 c.779G>T p.R260 DDLNVRCESEVFHACINWVKYDCEQ[p. QLRFYVQAL,KYDCEQLRF,LRFYVQALL,QLRFYVQALL,KYD LUAD L R260L]LRFYVQALLRAVRCHSLTPNFLQ CEQLRFY,WVKYDCEQLR,EQLRFYVQAL,VKYDCEQLRF,CE MQL QLRFYVQA KEL c.1231G>A p.V411 RKLSQKLRELTEQPPMPARPRWMKC[p. CMEETGTFF,KCMEETGTF,MKCMEETGTF,KCMEETGTFF GBM M V411M]MEETGTFFEPTLAALFVREAF GPSTR KHDR c.608C>T p.S203 LNGSEDSGRGRGIRGRGIRIAPTAP[p.S RIAPTAPLR,APLRGRGGA,PLRGRGGAI,IRIAPTAPL,GIRIAP LUAD BS2 L 203L]LRGRGGAIPPPPPPGRGVLTPRG TAPL,APLRGRGGAI STV KIAA0 c.188A>G p.K63R RKVAKEGGPKVTSRNFEKSITKLGK[p.K KSITKLGKR,ITKLGKRGV,RGVKQFKNK,LGKRGVKQF,ITKLG TGCT 020 63R]RGVKQFKNKQQGDKSPKNKFQPA KRGVK,LGKRGVKQFK,KLGKRGVKQF NKF KIAA0 c.359_360i p.T120f STPKRVPMGPIIVPPGGHSVPSTPP[p.T HSVPSTPPR,RSNQNREWCL STAD 182 nsC s 120fs]RGDHRSNQNREWCLEE* KIAA0 c.2706de|C p.I902f GLETGWNCHISLTPNGDMPGSEIPP[p.I APATQAPCM,SEIPPPAPA,APATQAPCMM,SEIPPPAPAT, STAD 195 s 902fs]PAPATQAPCMMT* MPGSEIPPPA KIAA0 c.2683de|A p.K895f PMNHDQFHLVPNHIWSAEGNISKK[p. ISKKQNALA,NISKKQNAL,KKQNALAEH STAD 240 s K895fs]QNALAEH* KIAA0 c.542G>A p.R181 YRAVIIHGFVEELVVNEDPEYQWID[p.R EYQWIDQIR,WIDQIRTPR,PEYQWIDQI,QWIDQIRTPR,YQ CRC 528 Q 181Q]QIRTPRASNEARQRLISLMSGEL WIDQIRTP,DPEYQWIDQI QRK KIAA0 c.3244C>T p.R108 SHSITIDFTHPCHVALIRIWNYNKS[p.R1 WIHSFRGVK,YNKSWIHSF,KSWIHSFRG,NKSWIHSFR,RIW CRC 556 2W 082W]WIHSFRGVKDITMLLDTQCIFEG NYNKSW,WNYNKSWI,NYNKSWIHSF,RIWNYNKSWI,KS EIA WIHSFRGV,SWIHSFRGVK,YNKSWIHSFR,IRIWNYNKSW KIAA0 c.988C>A p.L330I FPDQERMCSRPGSRRERPLSATRKT[p.L ATRKTICEA,RKTICEAEY,RPLSATRKTI,TRKTICEAEY UCEC 556 330I]ICEAEYPEEDASAVLQAIQVENAA LQ KIAA0 c.4775de|C p.A159 PRWESSATLRFTDAPCQDVSDAAVS[p. DVSDAAVSDL,SDLEDCSQSL STAD 586 2fs A1592fs]DLEDCSQSLSLSTMQEDMES SGADTF* KIAA0 c.1337A>C p.Q446 GQSPMGGPFIPAAPVKTALPAGPQP[p. QPPPQPQPPL BLCA 907 P Q446P]PPQPQPPLPSQPQAQKRRFTE ELPDE KIAA0 c.1546_154 p.R516f TGFSSQNEIEGAGSKPASSSGKERE[p.R TSLSSDWNK,LSSDWNKNR,QAVDASTSL,STSLSSDWNK, GBM 907 7de|AG s 516fs]GQAVDASTSLSSDWNKNRVR* SLSSDWNKNR,KEREGQAVDA,REGQAVDAST,GQAVDAST SL,DASTSLSSDW KIAA1 c.14039T>C p.L468 SMSLHGNHMTLACFHGPNFRSKSWA[p. RSKSWAPFH,KSWAPFHLE,FRSKSWAPF,SKSWAPFHL,NF CLL 109 0P p.L4680P]PFHLEEPNIAFWTEAQKIWE RSKSWAPF,RSKSWAPFHL,APFHLEEPNI DGSSDH KIAA1 c.14810C>A p.S493 ITYTTVDWRDFMCNTWHLEPTLRLI[p. RLIYWTGRK,LEPTLRLIY,LIYWTGRKI,EPTLRLIYW,HLEPTL CRC 109 7Y S4937Y]YWTGRKIDPVGVDYILQKLGF RLIY,RLIYWTGRKI,TLRLIYWTGR HHART KIAA1 c.4763de|A p.E158 ANSLLDRGMQLSGSTSNTPYTPLEK[p.E NSLITQMMK,EKNSLITQM,KNSLITQMM,TPLEKNSLI,KNS STAD 109 8fs 1588fs]NSLITQMMKH* LITQMMK,LEKNSLITQM,EKNSLITQMM KIAA1 c.446C>T p.A149 YFRKGPFFGLACFANMPVESELERG[p. GVRMKSVGI,SELERGVRM,VRMKSVGIL,VESELERGV,GVR UCEC 147 V A149V]VRMKSVGILSPSYTLLYRYMHFL MKSVGIL,LERGVRMKSV ENQ KIAA1 c.3608C>A p.P120 SVTVEISDSAPPAPLVKEVTKRFST[p.P1 FSTQDAAPV,KRFSTQDAA,VTKRFSTQDA LUAD 211 3Q 203Q]QDAAPVSTEPAWLALAKRKAKA WSDC KIAA1 c.924de|T p.R308f ERAPREEQQRSLEAPGWEDAERRER[p. RSASAWRRR,SASAWRRRR,KRRRGGGWR,GWRRTPGWR, CESC 211 s R308fs]RSASAWRRRRSEGVCRPRPKR GWRSGGGRR,RSGGGRRRR,SGGGRRRRK,RSSKGRRRR,S RRGGGWRRTPGWRSGGGRRRRKEDA SKGRRRRR,KGRRRRRLR,RRRRLRDGK,KSWNSRRRR,RRR RRSSKGRRRRRLRDGKSWNSRRRRCRG CRGRPR,RGRPRRWRR,RWRRLGRAG,LGRAGGARR,RAG RPRRWRRLGRAGGARRRRIWGKRRRR GARRRR,GARRRRIWG,ARRRRIWGK,RRRRIWGKR,RIWG ARRTWRTGGGSSVSF* KRRRR,RRRARRTWR,RARRTWRTG,DGKSWNSRR,RPRR WRRLG,RERRSASAW,RRLRDGKSW,RRRRARRTW,WRTG GGSSV,TGGGSSVSF,AERRERRSA,RTGGGSSVSF,RERRSAS AWR,RSASAWRRRR,AWRRRRSEGV,KRRRGGGWRR,RSG GGRRRRK,RSSKGRRRRR,SSKGRRRRRL,KGRRRRRLRD,RR RRRLRDGK,RLRDGKSWNS,KSWNSRRRRC,NSRRRRCRGR, RRRRCRGRPR,RRRCRGRPRR,RCRGRPRRWR,RGRPRRW RRL,RPRRWRRLGR,RWRRLGRAGG,LGRAGGARRR,RAGG ARRRRI,GARRRRIWGK,RIWGKRRRRA,RRRRARRTWR,RA RRTWRTGG,TWRTGGGSSV,DARRSSKGRR,DGKSWNSRR R,SWNSRRRRCR,RPRPKRRRGG,RPKRRRGGGW,ERRERR SASA,RRERRSASAW,RRRLRDGKSW KIAA1 c.926_927i p.E309f RAPREEQQRSLEAPGWEDAERRERE[p. RKMRGGAQK,KMRGGAQKA,REREGARAP,RQAGGAEAA, CESC 211 nsG s E309fs]GARAPGGGGGAKASAGPGPS AERREREGA,RAPGGGGGAK,KMRGGAQKAG,REREGARA GGEAAAGGGRQAGGAEAAGGGGRK PG,RQAGGAEAAG,RKMRGGAQKA MRGGAQKAGGGGG* KIAA1 c.413C>T p.S138 LRGWYNCLTLAIYGSVDRVISHDRD[p.S RVISHDRDF HNSC 429 F 138F]FPPPPPPPPPPQPQPSLKRNPK HAD KIAA1 c.4576G>A p.D152 VLSAPESLQNLFNNRTAYVLADVMD[p. VMDNQLKSM,MDNQLKSMW,VLADVMDNQL,DVMDNQ HNSC 429 6N D1526N]NQLKSMWFTPFQAEEIDTDL LKSM,VMDNQLKSMW,MDNQLKSMWF DLVKVD KIAA1 c.3816G>T p.L127 DGERLSAVKSSDLINKMDLQRAAII[p.L RAAIIFGYR,LQRAAIIFG,QRAAIIFGY,AAIIFGYRI,FGYRIQG LUAD 549 2F 1272F]FGYRIQGVIAQPVDRVKRPSPES VI,IIFGYRIQGV,RAAIIFGYRI,IFGYRIQGVI,LQRAAIIFGY,M QSN DLQRAAIIF KIAA1 c.189G>C p.L63F LQEAEDDVDPGHSSSVKELDTDADK[p. KFKKKTAEDR,KELDTDADKF LUSC 751 L63F]FKKKTAEDRTQAFHLRQNLSALD KMH KIAA1 c.291G>C p.K97N TQAFHLRQNLSALDKMHEEQELFTE[p. 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RQWWCTCRM,RMSGPSCLL,TLLDGTQKL,QTLLDGTQK,M STAD 967 s P415fs]GGFRQWWCTCRMSGPSCLL SGPSCLLW,LWRSGRPCA,RSGRPCASR,SGRPCASRK,ASRK WRSGRPCASRKLQRQLPQPRRHKGKR LQRQL,KGKRSLLNR,RSLLNRHLM,KLQRPPHSR,LQRPPHS SLLNRHLMPWSKQQTLLDGTQKLQRP RK,HSRKRTLIS,RTLISQRPL,SCLLWRSGR,MPWSKQQTL,P PHSRKRTLISQRPLHPP* PHSRKRTL,LQPGPPGGF,CRMSGPSCL,RQLPQPRRH,RRH KGKRSL,KRSLLNRHL,LLNRHLMPW,LLNRHLMPWS,HLMP WSKQQT,LMPWSKQQTL,RSGRPCASRK,KLQRPPHSRK,M SGPSCLLWR,YLQPGPPGGF,RMSGPSCLLW,SLLNRFILMP W,SGRPCASRKL,LQRQLPQPRR,RQLPQPRRHK,KGKRSLL NRH,LNRHLMPWSK,LQRPPHSRKR,HSRKRTLISQ,RTLISQ RPLH,GFRQWWCTCR,KLQRQLPQPR,MPWSKQQTLL,RPP FISRKRTL,FQYLQPGPPG,FRQWWCTCRM,RQWWCTCRM S,CRMSGPSCLL,RRHKGKRSLL,GKRSLLNRHL,KRSLLNRHL M,KRTLISQRPL KIAA2 c.1034G>T p.C345 NVRDKTTLLMQEDAQFNFFPSVFTT[p. SVFTTFPKR,TTFPKRESK,PSVFTTFPK,FFPSVFTTF,FTTFPK LUSC 022 F C345F]FPKRESKSGALKQSSDFSQFKVP RESK,NFFPSVFTTF,FPSVFTTFPK DVS KIAA2 c.1720C>T p.R574 PAKMILDNHDISVEMGVKSNYEIRI[p.R RICRPCEIK,ICRPCEIKK,SNYEIRICR,YEIRICRPC,RICRPCEIK UCEC 026 C 574C]CRPCEIKKTDCCKENLEKPRSPGE K,KSNYEIRICR,EIRICRPCEI VT KIAA2 c.2069de|A p.K690f LEQSLQSHKKLKLTKMRAKKKKKKK[p.K RAKKKKKKKR STAD 026 s 690fs]RN* KIDIN c.2552A>G p.N851 SNINGHDYMRNIVHLPVFLNSRGLS[p. FLNSRGLSS,GLSSARKFL,SARKFLVTS,NSRGLSSAR,LSSARK TGCT S220 S N851S]SARKFLVTSATNGDVPCSDTTGI FLV,RGLSSARKF,FLNSRGLSSA,GLSSARKFLV,NSRGLSSAR QED K,RGLSSARKFL,SARKFLVTSA,SRGLSSARKF KIF13 c.3345de|A p.K111 LNCVRERWSDALIKRREYLDEQIKK[p.K TMWSGKPSL,KQRTMWSGK,MWSGKPSLW,KQRKQRTM STAD A 5fs 1115fs]SAIKQRKQRTMWSGKPSLWSS W,RTMWSGKPS,SAIKQRKQR,IKQRKQRTM,YLDEQIKKSA, G* TMWSGKPSLW,KSAIKQRKQR,AIKQRKQRTM,KQRKQRT MWS,RKQRTMWSGK,KQRTMWSGKP,RTMWSGKPSL,QI KKSAIKQR,IKQRKQRTMW KIF14 c.1793G>A p.R598 VFTLVMTQTKTEFVEGEEHDHRITS[p.R RITSQINLI,SQINLIDLA,HRITSQINL,HRITSQINLI,SQINLIDL CRC Q 598Q]QINLIDLAGSERCSTAHTNGDRL AG KEG KIF15 c.754G>C p.E252 TSMNRESSRSHAVFTITIESMEKSN[p.E SMEKSNQIV,KSNQIVNIR,ESMEKSNQI,QIVNIRTSLL,ESM LUAD Q 252Q]QIVNIRTSLLNLVDLAGSERQKDT EKSNQIV,IESMEKSNQI,MEKSNQIVNI,NQIVNIRTSL HA KIF16 c.434G>A p.R145 GLIPRICEGLFSRINETTRWDEASF[p.R1 SFQTEVSYL,ASFQTEVSY,DEASFQTEV,QTEVSYLEIY,FQTE CRC B Q 45Q]QTEVSYLEIYNERVRDLLRRKSSKT VSYLEI,EASFQTEVSY,ASFQTEVSYL,DEASFQTEVS F KIF18 c.49C>T p.R17C MSVTEEDLCHHMKVVV[p.R17C]CVRP HMKVVVCVR,VVCVRPENTK,CVRPENTKEK,HHMKVVVCV CRC A ENTKEKAAGFHKVVHVVDKHIL R KIF1B c.3958C>T p.R132 TVTIIHEKGSELHWKDVRELVVGRI[p.R LVVGRIWNK,RELVVGRIW BRCA 0W 1320W]WNKPEVDEAAVDAILSLNIISA KYLK KIF20 c.160G>A p.E54K NFDGIKLDLSHEFSLVAPNTEANSF[p.E KSKDYLQVC,FKSKDYLQV,NTEANSFKSK,SFKSKDYLQV,KS UCEC B 54K]KSKDYLQVCLRIRPFTQSEKELESE KDYLQVCL,EANSFKSKDY G KIF20 c.2971G>A p.E991 NEIETATRSITNNVSQIKLMHTKID[p.E9 LMHTKIDKL,KLMHTKIDK,KLRTLDSVS,TKIDKLRTL,KLMHT CRC B K 91K]KLRTLDSVSQISNIDLLNLRDLSNGS KIDKL,HTKIDKLRTL,LMHTKIDKLR KIF23 c.1048G>A p.E350 KEQITISQLSLVDLAGSERTNRTRA[p.E3 RTNRTRAKG,RTRAKGNRL,RTRAKGNRLR,RAKGNRLREA BLCA K 50K]KGNRLREAGNINQSLMTLRTCMD VLR KIF23 c.449G>A p.R150 SPGEGGLLPRCLDMIFNSIGSFQAK[p.R FQAKQYVFK,SFQAKQYVF,IGSFQAKQY,SFQAKQYVFK,KQ UCEC Q 150Q]QYVFKSNDRNSMDIQCEVDALL YVFKSNDR,SIGSFQAKQY,GSFQAKQYVF ERQK KIF25 c.7T>A p.W3R MT[p.W3R]RTSGQLQREKQARPGSGA MTRTSGQLQ,RTSGQLQREK,MTRTSGQLQR PRAD VLAFPDDK KIF26 c.3194de|C p.S106 SLQSSRESLNSCGFVEGKPRPMGSP[p.S RLPPHCLPR,TSHPALLPR,RSTSHPALL,RGSCRLPPH,RARIP STAD B 5fs 1065fs]GWASPACPRPRSTSHPALLPR AWRL,STPRRGSCR,KPRPMGSPG,RPMGSPGWA,CPRPRS DAKSTPRRGSCRLPPHCLPRARIPAWRL TSH,RPRSTSHPA,HPALLPRDA,TPRRGSCRL,LPRARIPAW,I GSPCCSPRCVRPRLE* PAWRLGSP,SPRCVRPRL,LPPHCLPRA,RLPPHCLPRA,STSH PALLPR,RPRSTSHPAL,KSTPRRGSCR,RARIPAWRLG,WAS PACPRPR,LPRARIPAWR,RLGSPCCSPR,KPRPMGSPGW,R PMGSPGWAS,SPACPRPRST,IPAWRLGSPC,MGSPGWAS PA KIF26 c.3337G>A p.V111 RCKVYTQKGVLPSPAPLPPSSKDSG[p.V GMASRESLL,SGMASRESL,SSKDSGMASR,LPPSSKDSGM,S BRCA B 3M 1113M]MASRESLLQPEVRTPPVGMSP GMASRESLL QVLKK KIF26 c.3341C>T p.A111 CKVYTQKGVLPSPAPLPPSSKDSGV[p.A SSKDSGVVSR CRC B 4V 1114V]VSRESLLQPEVRTPPVGMSPQV LKKS KIF26 c.6097G>A p.A203 SKEAMCFNAKLKILEHRQQRIAEVR[p.A RTKYEWLMK,RIAEVRTKY,EVRTKYEWL,AEVRTKYEW,QQ LIHC B 3T 2033T]TKYEWLMKELEATKQYLMLDP RIAEVRTK,RTKYEWLMKE,RQQRIAEVRT,QRIAEVRTKY,AE NKWLS VRTKYEWL,TKYEWLMKEL,IAEVRTKYEW KIF27 c.2775G>T p.K925 LDACNLKRRKGSFGSIDHLQKLDEQ[p.K KLDEQNKWL,EQNKWLDEEV,LQKLDEQNKW UCEC N 925N]NKWLDEEVEKVLNQRQELEELE ADLK KIF9 c.1438G>A p.G480 ISAIQKAGLVDVDGHLVGEPEGQNF[p. NFRLGVAPF,GQNFRLGVA,RLGVAPFSTK,QNFRLGVAPF, LUAD R G480R]RLGVAPFSTKPGKKAKSKKTFKE GEPEGQNFRL PLS KIF9 c.1781G>A p.R594 IRPDTPPSKPVAFEEFKNEQGSEIN[p.R5 GSEINQIFK,QGSEINQIFK,EQGSEINQIF,NQIFKENKSI,NEQ UCEC Q 94Q]QIFKENKSILNERRKRASETTQHIN GSEINQI A KIRRE c.1003de|C p.P335f VDPKPTTTDIGSDVTLTCVWVGNPP[p. VWVGNPPSL,SPGPKRTQI,CVWVGNPPSL,SPGPKRTQIW STAD L s P335fs]SLSPGPKRTQIWS* KIRRE c.1810G>T p.G604 VDLKQDLRCDTIDTREEYEMKDPTN[p. EMKDPTNCY,PTNCYYNVR,MKDPTNCYY,YEMKDPTNC,D LUAD L C G604C]CYYNVRAHEDRPSSRAVLYADY PTNCYYNV,EMKDPTNCYY,YEMKDPTNCY RAPG KIRRE c.1947de|C p.V649 PPSPLGPPGTPTFYDFNPHLGMVPP[p. HMLPSPHLA,RLTCDIFPM,HLATRVSRL,ATRVSRLTC,LPSP STAD 12 fs V649fs]ADFTEPGQAISPHPTLELSPATS HLATR,ESWDLQLAI,HPTLELSPA,NPHPLGPQI,SPHLATRV NPHPLGPQIWPPGLPPSHMLPSPHLAT S,FPMEESWDL,LAIMDCSDF,LGMVPPADF,GQAISPHPT,Q RVSRLTCDIFPMEESWDLQLAIMDCSD AISPHPTL,SHMLPSPHL,VSRLTCDIF,MEESWDLQL,EPGQ F* AISPH,EESWDLQLA,DIFPMEESW,AISPHPTLEL,HLATRVS RLT,IFPMEESWDL,MLPSPHLATR,ESWDLQLAIM,NPHLG MVPPA,SPATSNPHPL,WPPGLPPSHM,LPSPHLATR,QLAI MDCSDF,HLGMVPPADF,ADFTEPGQAI,GQAISPHPTL,HM LPSPFILAT,RVSRLTCDIF,SRLTCDIFPM,EESWDLQLAI,HPT LELSPAT,NPHPLGPQIW,FPMEESWDLQ,MEESWDLQLA KIT c.1669T>G p.W55 VAGMMCIIVMILTYKYLQKPMYEVQ[p. PMYEVQGKV,VQGKVVEEI,EVQGKVVEEI,KPMYEVQGKV TGCT 7G W557G]GKVVEEINGNNYVYIDPTQLPY DHKW KIT c.2446G>C p.D816 RDLAARNILLTHGRITKICDFGLAR[p.D8 HIKNDSNYV,RHIKNDSNY,CDFGLARHI,HIKNDSNYVV,AR TGCT H 16H]HIKNDSNYVVKGNARLPVKWMA HIKNDSNY,RHIKNDSNYV PESI KIT c.2446G>T p.D816 RDLAARNILLTHGRITKICDFGLAR[p.D8 ICDFGLARY,YIKNDSNYV,RYIKNDSNY,DFGLARYIK,CDFGL TGCT Y 16Y]YIKNDSNYVVKGNARLPVKWMAP ARYI,YIKNDSNYVV,KICDFGLARY,RYIKNDSNYV,ARYIKND ESI SNY KIT c.2447A>T p.D816 RDLAARNILLTHGRITKICDFGLAR[p.D8 VIKNDSNYV,RVIKNDSNY,CDFGLARVI,RVIKNDSNYV,VIK LAML,TGCT V 16V]VIKNDSNYVVKGNARLPVKWMA NDSNYVV,ARVIKNDSNY PESI KIT c.2464A>T p.N822 NILLTHGRITKICDFGLARDIKNDS[p.N8 KNDSYYVVK,SYYVVKGNA,RDIKNDSYY,YYVVKGNAR,DIK TGCT Y 22Y]YYVVKGNARLPVKWMAPESIFNC NDSYYV,IKNDSYYVV,YYVVKGNARL,LARDIKNDSY,SYYVV VYT KGNAR,DIKNDSYYVV,DSYYVVKGNA KIT c.2466T>G p.N822 NILLTHGRITKICDFGLARDIKNDS[p.N8 KNDSKYVVK,RDIKNDSKY,IKNDSKYVV,KYVVKGNARL,LAR TGCT K 22K]KYVVKGNARLPVKWMAPESIFNC DIKNDSK VYT KLC2 c.1703de|C p.T568f SFGKLRDALRRSSEMLVKKLQGGTP[p.T TPRSPLTPG,LQGGTPRSPL STAD s 568fs]RSPLTPG* KLF3 c.312de|A p.I104f SLKFPSSHRRASPGLSMPSSSPPIK[p.I1 LLQACSPSA,QACSPSACR,PPIKNTHPL,SPSACRCPC,LQAC STAD s 04fs]NTHPLLQACSPSACRCPCHQ* SPSAC,SPPIKNTHPL KLF3 c.671_672i p.S224f GIEPQRTDYYPEEMSPPLMNSVSPP[p. LMNSVSPPA,SVSPPASIV,TFTCGIPGY,NSVSPPASI,FTCGIP STAD nsC s S224fs]ASIVARESPFGHRAAWEETFTC GYS,SPFGHRAAW,SIVARESPF,RESPFGHRA,HRAAWEETF, GIPGYSKEAEDTQM* SKEAEDTQM,WEETFTCGI,PLMNSVSPPA,FTCGIPGYSK,V ARESPFGHR,ETFTCGIPGY,NSVSPPASIV,ASIVARESPF,LM NSVSPPAS,MNSVSPPASI,RESPFGHRAA,GHRAAWEETF,Y SKEAEDTQM KLF4 c.1300A>C p.K434 GRRSWPRKRTATHTCDYAGCGKTYT[p. KTYTQSSHL,TQSSHLKAH,KTYTQSSHLK,QSSHLKAHLR,GK BRCA Q K434Q]QSSHLKAHLRTHTGEKPYHCD TYTQSSHL,TQSSHLKAHL WDGCG KLF5 c.1255G>C p.E419 LRTHTGEKPYKCTWEGCDWRFARSD[p. RSDQLTRHY,FARSDQLTR,DQLTRHYRK,WRFARSDQL,RS LUAD,LUSC Q E419Q]QLTRHYRKHTGAKPFQCGVCN DQLTRHYR,ARSDQLTRHY RSFSR KLF5 c.353C>T p.S118 EKYLTPQLPPVPIIPEHKKYRRDSA[p.S1 KYRRDSALV,SALVVDQFF,KKYRRDSAL,YRRDSALVV,KYRR BLCA L 18L]LVVDQFFTDTEGLPYSINMNVFLP DSALVV,HKKYRRDSAL,KKYRRDSALV,RDSALVVDQF DI KLHD c.962G>C p.W32 DAWTYCISKNEWIQFNHPYTEKPRL[p. KPRLSHTAC,KPRLSHTACA,TEKPRLSHTA TGCT C2 1S W321S]SHTACASDEGEVIVFGGCANN LLVHH KLHD c.1903G>A p.E635 DRWDFAPPLPSDTFALAHTATVRAK[p. HTATVRAKK,TVRAKKIFV,RAKKIFVTG,KIFVTGGSL,KIFVT SKCM C7A K E635K]KIFVTGGSLRFLLFRFSAQEQRW GGSLR,TVRAKKIFVT,RAKKIFVTGG,HTATVRAKKI,KKIFVT WAG GGSL KLHL1 c.637G>A p.E213 FLISGVTLDNCVEVGRIANTYNLTE[p.E2 NLTEMDKYV,EMDKYVNSF,ANTYNLTEM,TEMDKYVNS, UCEC 3 K 13K]MDKYVNSFVLKNFPALLSTGEFLKL MDKYVNSFV,NTYNLTEMDK,TEMDKYVNSF,IANTYNLTE P M,MDKYVNSFVL KLHL1 c.693de|C p.P231f KYLVEDVLLLNFEEMRALLDSLPPP[p.P WSRSWRSSR,SWRSSRCPC,TARPACSMR,DSLPPPWSR,TT STAD 4 s 231fs]WSRSWRSSRCPCCGWSTTARP ARPACSM,RPACSMRLT,LLDSLPPPW,LPPPWSRSW,TTAR ACSMRLTS* PACSMR,RSWRSSRCPC,SWRSSRCPCC,SSRCPCCGWS,ST TARPACSM,TARPACSMRL,RPACSMRLTS,ALLDSLPPPW,S LPPPWSRSW,RSSRCPCCGW KLHL1 c.554A>G p.D185 DNFVPLMSRPDFLSYLSFEKLMSYL[p.D MSYLGNDHL,LMSYLGNDH,LGNDHLSRF,FEKLMSYLG,LM BLCA 5 G 185G]GNDHLSRFPEIELYEAVQSWLRH SYLGNDHL,YLGNDHLSRF,SYLGNDHLSR DRR KLHL2 c.97G>A p.E33K YMLANLTHLHSEQLLQGLNLLRQHH[p. KLCDIILRV,LNLLRQHHK,NLLRQHHKL,RQHHKLCDI,GLNLL UCEC 8 E33K]KLCDIILRVGDVKIHAHKVVLASV RQHHK,RQHHKLCDII SP KLHL5 c.976C>T p.R326 QLSQVVEACCKFLMKQLHPSNCLGI[p. SNCLGICSF CRC C R326C]CSFADAQGCTDLHKVAHNYTM EHFME KLK2 c.169C>A p.P57T EKHSQPWQVAVYSHGWAHCGGVLVH VLVHTQWVL,GVLVHTQWV,HTQWVLTAA,TQWVLTAAH, CRC [p.P57T]TQWVLTAAHCLKKNSQVWL VHTQWVLTAA GRHNLFE KLK2 c.481G>A p.E161 VKVLGLPTQEPALGTTCYASGWGSI[p.E YASGWGSIK,SIKPEEFLR,GSIKPEEFLR,GWGSIKPEEF CESC K 161K]KPEEFLRPRSLQCVSLHLLSNDMC AR KLK6 c.359G>A p.R120 QSSVVRAVIHPDYDAASHDQDIMLL[p. MLLHLARPA,LLHLARPAK,DIMLLHLAR,IMLLHLARPA,LLH GBM H R120H]HLARPAKLSELIQPLPLERDCSA LARPAKL,MLLHLARPAK,HDQDIMLLHL NTT KPNA c.86G>A p.R29Q NEKLDNQRLKNFKNKGRDLETMRRQ[p. QQNEVVVEL,TMRRQQNEV,RRQQNEVVV,RQQNEVVVE, CRC 4 R29Q]QNEVVVELRKNKRDEHLLKRRN TMRRQQNEVV,ETMRRQQNEV,MRRQQNEVVV,RQQNE VPHE VVVEL KPRP c.1659_166 p.E553f YCGPSSYNQGQESGAGCGPGDVFPE[p. GSKECLFLK,WPWRPRQCL,RPRQCLCWS,SERGSKECL,FPE HNSC 0insC s E553fs]PEGSGWPWRPRQCLCWSER PEGSGW,EPEGSGWPW,CLCWSERGSK,RGSKECLFLK,EGS GSKECLFLKER* GWPWRPR,SERGSKECLF KRAS c.176C>G p.A59G PTIEDSYRKQVVIDGETCLLDILDT[p.A5 LDTGGQEEY,GGQEEYSAM,ILDTGGQEEY MM 9G]GGQEEYSAMRDQYMRTGEGFLCV FAI KRAS c.180_181T p.Q61K IEDSYRKQVVIDGETCLLDILDTAG[p.Q6 LDTAGKEEY,AGKEEYSAM,LDTAGKEEY,DTAGKEEYSA CRC,THCA C>AA IK]KEEYSAMRDQYMRTGEGFLCVFAI NNT KRAS c.182A>G p.Q61R IEDSYRKQVVIDGETCLLDILDTAG[p.Q6 LDTAGREEY,AGREEYSAM,ILDTAGREEY,AGREEYSAMR,D MM,TGCT 1R]REEYSAMRDQYMRTGEGFLCVFAI TAGREEYSA NN KRAS c.182A>T p.Q61L IEDSYRKQVVIDGETCLLDILDTAG[p.Q6 LDTAGLEEY,AGLEEYSAM,ILDTAGLEEY,LLDILDTAGL,DTA CRC,LUAD, 1L]LEEYSAMRDQYMRTGEGFLCVFAIN GLEEYSA TGCT N KRAS c.183A>C p.Q61H IEDSYRKQVVIDGETCLLDILDTAG[p.Q6 LDTAGHEEY,AGHEEYSAM,ILDTAGHEEY,DTAGHEEYSA LUAD,PAAD, 1H]HEEYSAMRDQYMRTGEGFLCVFAI STAD NN KRAS c.183A>T p.Q61H IEDSYRKQVVIDGETCLLDILDTAG[p.Q6 LDTAGHEEY,AGHEEYSAM,ILDTAGHEEY,DTAGHEEYSA MM,TGCT 1H]HEEYSAMRDQYMRTGEGFLCVFAI NN KRAS c.34G>A p.G12S MTEYKLVVVGA[p.G12S]SGVGKSALTI LVVVGASGV,KLVVVGASGV,YKLVVVGASG CRC,STAD QLIQNHFVDEYDPTIE KRAS c.34G>C p.G12R MTEYKLVVVGA[p.G12R]RGVGKSALTI ARGVGKSAL,KLVVVGARGV,VVVGARGVGK,EYKLVVVGA MM,PAAD, QLIQNHFVDEYDPTIE R,GARGVGKSAL,RGVGKSALTI TGCT KRAS c.34G>T p.G12C MTEYKLVVVGA[p.G12C]CGVGKSALTI LVVVGACGV,VVGACGVGK,KLVVVGACGV,VVVGACGVG CRC,LUAD QLIQNHFVDEYDPTIE K KRAS c.35G>A p.G12D MTEYKLVVVGA[p.G12D]DGVGKSALT LVVVGADGV,VVGADGVGK,KLVVVGADGV,VVVGADGVG CESC,CRC, IQLIQNHFVDEYDPTIE K GBM,KIRP, LAML,LUAD, MM,PAAD, STAD, UCEC,UCS KRAS c.35G>C p.G12A MTEYKLVVVGA[p.G12A]AGVGKSALTI LVVVGAAGV,VVGAAGVGK,YKLVVVGAA,KLVVVGAAGV, CRC,LUAD,MM, QLIQNHFVDEYDPTIE VVVGAAGVGK,YKLVVVGAAG,GAAGVGKSAL TGCT,UCEC KRAS c.35G>T p.G12V MTEYKLVVVGA[p.G12V]VGVGKSALTI LVVVGAVGV,VVGAVGVGK,YKLVVVGAV,KLVVVGAVGV, BRCA,CESC, QLIQNHFVDEYDPTIE VVVGAVGVGK,GAVGVGKSAL CRC,LUAD, OV,PAAD,TGCT, UCEC,UCS KRAS c.37G>T p.G13C MTEYKLVVVGAG[p.G13C]CVGKSALTI VVGAGCVGK,KLVVVGAGCV,VVVGAGCVGK LUAD QLIQNHFVDEYDPTIED KRAS c.38G>A p.G13D MTEYKLVVVGAG[p.G13D]DVGKSALT VVGAGDVGK,KLVVVGAGDV,VVVGAGDVGK CESC,CLL, IQLIQNHFVDEYDPTIED CRC,DLBCL, LUAD,MM, STAD,UCEC KRAS c.436G>A p.A146 PSRTVDTKQAQDLARSYGIPFIETS[p.A1 ETSTKTRQR,GIPFIETSTK,ETSTKTRQRV CRC,MM,TGCT T 46T]TKTRQRVEDAFYTLVREIRQYRLKK 1 KRBA c.2515A>G p.R839 DRLATALAGLAQEVATMRTQVNRLG[p. RTQVNRLGG,TQVNRLGGR,RTQVNRLGGR TGCT 1 G R839G]GRPQGPGPMGQASWMWTL PRGPRWAH KRT2 c.896T>G p.L299 KRTAAENDFVTLKKDVDNAYMIKVE[p. YMIKVEWQS,MIKVEWQSK,IKVEWQSKV,VEWQSKVDL,N KIRC W L299W]WQSKVDLLNQEIEFLKVLYDAE AYMIKVEW,MIKVEWQSKV,YMIKVEWQSK,VEWQSKVDL ISQI L KRT4 c.462_463i p.F154f RGNKSISMSVAGSRQGACFGGAGGF[p. WLWWWIWGL,GGFRHWWLW,GFRHWWLWW,FRHW KIRC nsC s F154fs]RHWWLWWWIWGLLQW* WLWWW,RHWWLWWWI,HWWLWWWIW,LWWWIW GLL,WWIWGLLQW,CFGGAGGFR,GGAGGFRHW,WLWW WIWGLL,AGGFRHWWLW,GFRHWWLWWW,RHWWLW WWIW,WWLWWWIWGL,WWWIWGLLQW,FGGAGGFR HW KRT6B c.590T>C p.L197 NKFASFIDKVRFLEQQNKVLDTKWT[p. VLDTKWTPL,KVLDTKWTPL CRC P L197P]PLQEQGTKTVRQNLEPLFEQYIN NLR KRT8 c.175T>G p.S59A TQKSYKVSTSGPRAFSSRSYTSGPG[p.S RSYTSGPGA,GARISSSSF,SYTSGPGAR,YTSGPGARI,RSYTS ACC,KIRP, 59A]ARISSSSFSRVGSSNFRGGLGGGY GPGAR,SYTSGPGARI,GARISSSSFS LIHC GG KRTAP c.346A>G p.I116V CGTGCGIGGGIGYGQEGSSGAVSTR[p.I VSTRVRWCR,STRVRWCRP,RVRWCRPDC,GAVSTRVRW, TGCT 1-1 116V]VRWCRPDCRVEGTCLPPCCVVS AVSTRVRWCR,STRVRWCRPD,RVRWCRPDCR,SGAVSTR CTPP VRW KRTAP c.372G>T p.M12 ACQSESSSAGLACVSQPCQSESTQQ[p. CQSESTQQI,ESTQQIGFV,SESTQQIGF,QSESTQQIGF,QQI LUAD 27-1 4I M124I]IGFVAQSCQPASLKGNSCPPKT GFVAQSC,SESTQQIGFV SKSK KRTAP c.144C>G p.S48R TCCRPSCCETTCCRTTYCRPSCCVS[p.S4 VSRCCRPQC GBM,PRAD 4-11 8R]RCCRPQCCQSVCCQPTCCRPRCCIS S KRTAP c.220A>T p.S74C VCYQPTCCHPSCCISSCCRPYCCES[p.S7 CESCCCRPC KIRP 4-5 4C]CCCRPCCCQTTCCRTTCCRTTCCCP S KRTAP c.272G>T p.C91F CRPYCCESSCCRPCCCQTTCCRTTC[p.C TCCRTTCFR,TTCCRTTCFR LUAD 4-5 91F]FRTTCCCPSCCVSSCCRPQCCQSV CC KRTAP c.188C>G p.T63S TCYRPSYSVSCCCRPQCCQSVCCQP[p.T SVCCQPSCCR TGCT 4-8 63S]SCCRPSCCVSSCCKPQCCQSVCCQ PT KRTAP c.53A>T p.D18V MVSSCCGSVCSDQGCGQ[p.D18V]VLC CSDQGCGQV,SDQGCGQVL,QVLCQETCCR PRAD 4-9 QETCCRPSCCETTCCRTTCCRPS KRTAP c.578C>A p.S193 GSCGGSKGGCGSCGGCKGGCGSCGG[p. GGCGSCGGY,KGGCGSCGGY LUAD 5-1 Y S193Y]YKGGCGSGCGGCGSGCGVPV CCCSCS KSR2 c.1664C>T p.T555 FNLPASHYYKYKQQFIFPDVVPVPE[p.T MPTRAPQVI,FPDVVPVPEM,MPTRAPQVIL,PEMPTRAPQ HNSC M 555M]MPTRAPQVILHPVTSNPILEGNP V LLQ L1CA c.1894C>A p.R632 LVVGSPGPVPRLVLSDLHLLTQSQV[p.R LLTQSQVSV,QVSVSWSPA,TQSQVSVSW,SQVSVSWSP,HL LUAD M S 632S]SVSWSPAEDHNAPIEKYDIEFEDK LTQSQVSV,SQVSVSWSPA,LTQSQVSVSW EM L1CA c.557C>T p.T186 PPSAEPLRIYWMNSKILHIKQDERV[p.T MMGQNGNLY,VMMGQNGNL,HIKQDERVM,IKQDERVM CRC M M 186M]MMGQNGNLYFANVLTSDNHS M,VMMGQNGNLY,MMGQNGNLYF,RVMMGQNGNL,LH DYICHA IKQDERVM L2HG c.1321_132 p.P441 VEDFVFDAGVGDIGNRILHVRNAPS[p.P HVRNAPSAA,SAATSSIAI,APSAATSSI,LHVRNAPSA,IL TGCT DH 3de|CCT de| 441de|]AATSSIAISGMIADEVQQRFEL HVRNAPSA,HVRNAPSAAT,NAPSAATSSI,APSAATSSIA,LHVRN * APSAA L3MB c.485G>T p.W16 HPVGWCEKTKHELHIPKGYRKDKFV[p. VLMDYLKAC,LMDYLKACK,KFVLMDYLK,KDKFVLMDY,YR LUAD TL4 2L W162L]LMDYLKACKLQNAPKKLFRNR KDKFVLM,LMDYLKACKL,VLMDYLKACK,KGYRKDKFVL,RK SPNGP DKFVLMDY LACTB c.13A>C p.M5L MYRL[p.M5L]LSAVTARAAAPGGLASS LLSAVTARA,RLLSAVTAR,YRLLSAVTA,RLLSAVTARA,LLSA ACC CGRRGVHQR VTARAA,MYRLLSAVTA,LSAVTARAAA LALBA c.121G>A p.A41T AILAKQFTKCELSQLLKDIDGYGGI[p.A4 TLPELICTM,IDGYGGITL,GYGGITLPEL,TLPELICTMF,ITLPE CRC 1T]TLPELICTMFHTSGYDTQAIVENNES LICTM LAMA c.3088G>T p.D103 NTCDPETGECVCPPHTQGVKCEECE[p. GVKCEECEY,CEYGHWGYDA,EECEYGHWGY LUAD 1 0Y D1030Y]YGHWGYDAEVGCQACNCSL VGSTHHR LAMA c.1673C>T p.A558 SLSTSADSLTTPRLTLSELDDIIKN[p.A55 ELDDIIKNV,NVSGIYAEI,IIKNVSGIY,DIIKNVSGI,IKNVSGIY CRC 4 V 8V]VSGIYAEIDGAKSELQVKLSNLSNLS A,IIKNVSGIYA,DIIKNVSGIY,KNVSGIYAEI,SELDDIIKNV LAMA c.1915G>A p.E639 NGLVQKALDASNVYENIVNYVSEAN[p. VNYVSEANK,YVSEANKTA,EANKTAEFA,SEANKTAEF,IVNY BLCA 4 K E639K]KTAEFALNTTDRIYDAVSGIDTQ VSEANK,EANKTAEFAL,VSEANKTAEF,SEANKTAEFA IIY LAMA c.3879G>A p.M12 PNGLLFYYASGSDVFSISLDNGTVI[p.M SLDNGTVII,VIIDVKGIK,TVIIDVKGI,VIIDVKGIKV,TVIIDVK LUSC 4 93I 1293I]IDVKGIKVQSVDKQYNDGLSHFV GIK,ISLDNGTVII ISS LAMA c.6668T>G p.L222 SSMAWARLHRLNASIADLQSQLRSP[p. QLRSPRGPR,LQSQLRSPR,SPRGPRHET,SQLRSPRGPR,QL KIRP 5 3R L2223R]RGPRHETAQQLEVLEQQSTSL RSPRGPRH,DLQSQLRSPR,SPRGPRHETA GQDAR LAMB c.1762G>T p.G588 GLAPLGSETFGQSPAVHVVLGEPVP[p. GEPVPWNPV,VVLGEPVPW,HVVLGEPVPW,EPVPWNPVT LUAD 4 W G588W]WNPVTWTGPGFARVLPGAGL W RFAVNN LAMB c.3715G>T p.G123 EADFKDLRGNVSEIERILKHPVFPS[p.G1 VFPSWKFLK,KHPVFPSWK,FPSWKFLKV,HPVFPSWKF,LKH LUAD 4 9W 239W]WKFLKVKDYHDSVRRQIMQLN PVFPSW,WKFLKVKDY,PVFPSWKFLK,KHPVFPSWKF,VFPS EQLKA WKFLKV,SWKFLKVKDY,HPVFPSWKFL,ILKHPVFPSW LAMC c.521_522C p.P174 KRSRADGPWEPYQFYSASCQKTYGR[p.P TYGRQEGQY,YGRQEGQYL,KTYGRQEGQY,TYGRQEGQYL, TGCT 3 C>AG Q 174Q]QEGQYLRPGEDERVAFCTSEFS RQEGQYLRPG DISPL LARP1 c.668_669i p.A223 PRHIPANRGEIKGSESATYVPVAPP[p.A APPHPSLAT,SLATRDQTGA,ATYVPVAPPH,ATRDQTGACL, STAD nsC fs 223fs]HPSLATRDQTGACLARPG* VPVAPPHPSL LARP4 c.487de|A p.T163f PENSETGGNESQPDSQEDPREVLKK[p. CILYHRWIV,VLKKHWNSA,YLGRTLLVT,ILYHRWIVT,VTSM STAD B s T163fs]HWNSAYLGRTLLVTCILYHRWI CQSQR,AYLGRTLLV,RTLLVTCIL,LYHRWIVTS,SAYLGRTLL, VTSMCQSQRWLTSTTSRSSALMWT* RWLTSTTSR,STTSRSSAL,TTSRSSALM,LKKHWNSAY,TLLV TCILY,HWNSAYLGR,LVTCILYHR,YHRWIVTSM,KKHWNSA YL,NSAYLGRTL,SMCQSQRWL,CQSQRWLTS,SQRWLTSTT, TSRSSQLMW,TSMCQSQRW,SAYLGRTLLV,RTLLVTCILY,L YHRWIVTSM,STTSRSSALM,VLKKHWNSAY,LLVTCILYHR,I VTSMCQSQR,EVLKKHWNSA,NSAYLGRTLL,LKKHWNSAY L,WNSAYLGRTL,CQSQRWLTST,SQRWLTSTTS,REVLKKH WNS,TTSRSSALMW LARS c.554_555i p.P185f MKSLGLSDEEIVKFSEAEHWLDYFP[p.P ATGYSGFKK,RLASFLHHH,GFEGRLASF,FPATGYSGF,LDYF KIRC nsC s 185fs]ATGYSGFKKNGFEGRLASFLHHH PATGY,FEGRLASFL,WLDYFPATGY,YFPATGYSGF,NGFEG * RLASF,AEHWLDYFPA,FKKNGFEGRL LAT2 c.53T>G p.L18W MSSGTELLWPGAALLVL[p.L18W]WG AALLVLWGV,VLWGVAASL,LLVLWGVAA,GAALLVLWGV, GBM VAASLCVRCSRPGAKRSEKIYQQR ALLVLWGVAA,LVLWGVAASL,WPGAALLVLW LBX1 c.526C>T p.R176 SPADRDQIAQQLGLTNAQVITWFQN[p. VITWFQNWR,QVITWFQNW,WFQNWRAKL,TWFQNWR CRC W R176W]WRAKLKRDLEEMKADVESAK AK,ITWFQNWRA,ITWFQNWRAK,QVITWFQNWR,TWFQ KLGPSG NWRAKL,WFQNWRAKLK,NWRAKLKRDL,AQVITWFQNW LCP1 c.1334_133 p.P445f SDALVIFQLYEKIKVPVDWNRVNKP[p.P RVNKPAIPQT KIRC 5insC s 445fs]AIPQTGRQYEEA* LHCG c.47T>A p.L16Q MKQRFSALQLLKLLL[p.L16Q]QLQPPL QLLKLLLQL,LLLQLQPPL,QLQPPLPRA,KLLLQLQPPL,QLQP TGCT R PRALREALCPEPCNCVPDGA PLPRAL,LQLLKLLLQL,LQLQPPLPRA LILRA c.1228C>T p.H410 SPVTSAHSGTYRCYGSLSSNPYLLS[p.H4 SSNPYLLSY,LLSYPSDSL,SYPSDSLEL,YPSDSLELM,NPYLLSY BLCA 1 Y 10Y]YPSDSLELMVSGAAETLSPPQNKS PS,LSSNPYLLSY,YLLSYPSDSL,SYPSDSLELM,LSYPSDSLEL,Y DS PSDSLELMV LILRB c.1417_141 p.L479 GLGRHLGVVIGILVAVILLLLLLLL[p.L479 ILLLLLLLLF BLCA 1 9de|CTC de| de|]FLILRHRRQGKHWTSTQRKADFQH PAGA LILRB c.1792T>C p.S598 TKDRQAEEDRQMDTERVLSSPGPQA[p. APPPPPRSL,PPPPPRSLPL PRAD 5 P S598P]PPPPPRSLPLTLPRCRLLHLKPP RM* LIM2 c.448T>A p.S150 IMAFAHQPTFSRISRPFSAGIMFFS[p.S1 GIMFFSTTL,MFFSTTLFV,FFSTTLFVV,IMFFSTTLF,FSTTLFV LUAD T 50T]TTLFVVLALAIVTGVTVSFLGRRFG VL,STTLFVVLA,TTLFVVLAL,IMFFSTTLFV,MFFSTTLFVV,GI D MFFSTTLF,FFSTTLFVVL,FSAGIMFFST,FSTTLFVVLA,STTLF VVLAL,TTLFVVLALA,AGIMFFSTTL LIMK2 c.608G>A p.R203 TTVQVKEVNRMHISPNNRNAIHPGD[p. NAIHPGDHI,HPGDHILEI,AIHPGDHIL,HILEINGTPV GBM H R203H]HILEINGTPVRTLRVEEVEDAIS QTS LIN9 c.547C>T p.R183 FCVCLKESFPNLKTRKLTRVEWGKI[p.R RVEWGKIWR,IWRLMGKPR,VEWGKIWRL,WGKIWRLMG UCEC W 183W]WRLMGKPRRCSSAFFEEERSAL K,KIWRLMGKPR,IWRLMGKPRR,VEWGKIWRLM KQKR LIN9 c.691G>A p.E231 QKRQKIRLLQQRKVADVSQFKDLPD[p. SQFKDLPDK,LPDKIPLPL,KDLPDKIPL,VSQFKDLPDK,SQFK CESC K E231K]KIPLPLVIGTKVTARLRGVHDGL DLPDKI,FKDLPDKIPL,LPDKIPLPLV FTG LINGO c.1228C>A p.P410 PDTIRERSFKDFHSTALSFYFTCKK[p.P4 KTKIREKKL,FTCKKTKIR,FYFTCKKTKI,SFYFTCKKTK,TCKKT HNSC 2 T 10T]TKIREKKLQHLLVDEGQTVQLECSA KIREK,YFTCKKTKIR D LIPJ c.707C>A p.P236 GSKLCPLQIFDKICLNILFMMFGYD[p.P FMMFGYDQK,DQKNLNMSR,MMFGYDQKN,MMFGYDQ LUAD Q 236Q]QKNLNMSRLDVYFSHNPAGTSV KNL,LFMMFGYDQK,FGYDQKNLNM QNML LLGL2 c.2864_286 p.P955f PRCLVDSAETKNHRPGNGAGPKKAP[p. KKAPEPSQEL BLCA 5insG s P955fs]EPSQELRDSE* LMLN c.595G>T p.G199 PVIVPEEHLQQCRVYRGGKWPHGAV[p. GKWPHGAVC,GKWPHGAVCV LUSC C G199C]CVPDQEGISDADFVLYVGALA TERCS LMX1 c.844_846d p.Q285 RHQQQQEQQNSQRLGQGEPGPGQGL LQEVLSSRM,GLQEVLSSRM THCA B e|CAG de| [p.Q285de|]QEVLSSRMEGMMASYTP LAPPQQQIVAM LOC10 c.1594A>C p.T532 ADDNLKTPSERQLTALPPSADDNIK[p.T DNIKPPAER,NIKPPAERLR,PPAERLRGPL LIHC 01322 P 532P]PPAERLRGPLPPSADDNLKTPSER 47 QL LOC15 c.268C>T p.P90S AEGIAMLLGTAGPSRLPAAPDASQA[p. SLRSPWALS,APDASQASL,SQASLRSPW,ASLRSPWAL,SLR CESC 1174 P90S]SLRSPWALSVAAALCSPVSCHPC SPWALSV,SQASLRSPWA,ASQASLRSPW GRH LOC40 c.430C>A p.L144 CVLAPGSGSRPTPHIVYSVPAARTC[p.L AARTCMGAPG,RTCMGAPGSL,VPAARTCMGA,YSVPAAR TGCT 1296 M 144M]MGAPGSLSPCHLCVHICAHTYS TCM GTPV LOC55 c.438_458d p.RAP LSVGDVDDTQCVRLDSDATSPRMEP[p. RMEPEGPEY,RMEPEGPEYW PRAD 4223 e|GCGGGC WMEQ RAPWMEQ147de|]EGPEYWEEETGTA GCCGTGGA 147de| KAKAQFYRVNLRTLSGYYNQSEA* TGGAGCA LOC64 c.278G>A p.G93E AGEDGRMIASQVVDINLAAEPKVNR[p. KVNRENAGV,VNRENAGVK,KVNRENAGVK,RENAGVKRS SKCM 9330 G93E]ENAGVKRSAAEMYGSSFDLDYG A FQRD LPHN c.2716T>A p.F906I EFIFLIGIDKTKYAIACPIFAGLLH[p.F906 GLLHIFFLA,LLHIFFLAA,HIFFLAAFA,IFAGLLHIF,IFFLAAFA TGCT 2 I]IFFLAAFAWMCLEGVQLYLMLVEVFE W,LHIFFLAAF,FAGLLHIFF,GLLHIFFLAA,IFAGLLHIFF,IFFLA AFAWM,CPIFAGLLHI,LLHIFFLAAF,PIFAGLLHIF,HIFFLAAF AW LPHN c.2220G>T p.E740 FPENMGHGSTIQLSANTLKQNGRNG[p. DIRVAFVLY,KQNGRNGDI,RNGDIRVAF,GDIRVAFVL,GRN LUAD 3 D E740D]DIRVAFVLYNNLGPYLSTENAS GDIRVAF,GDIRVAFVLY MKLG LPHN c.2477G>A p.R826 VFTVKHIKQSEENFNPNCSFWSYSK[p.R YSKHTMTGY,CSFWSYSKH,HTMTGYWST,FWSYSKHTM,S PRAD 3 H 826H]HTMTGYWSTQGCRLLTTNKTHT KHTMTGYW,SFWSYSKHTM,SYSKHTMTGY,WSYSKHTMT TCSC G,YSKHTMTGYW LPHN c.3548G>A p.R118 SGSRTPGRYSTGSQSRIRRMWNDTV[p. RMWNDTVQK,VQKQSESSF,TVQKQSESSF,RMWNDTVQ CRC 3 3Q R1183Q]QKQSESSFITGDINSSASLNRE KQ,VQKQSESSFI GLLN LPIN1 c.2921C>T p.S974 SDTFSNFTFWREPLPPFENQDIHSA[p.S FENQDIHSAL BLCA L 974L]LA* LPPR2 c.556G>T p.A186 TDQGACAGSPSLVAAARRAFPCKDA[p. SLCAYAVTY,DASLCAYAV,CKDASLCAY,SLCAYAVTYT,RAF ACC S A186S]SLCAYAVTYTAMYVTLVFRVKG PCKDASL,ASLCAYAVTY,FPCKDASLCA,KDASLCAYAV SRLV LPPR4 c.1579C>A p.R527 LKIQPGAVPGCNNSMPGGPRVSIQS[p. RVSIQSSPG,IQSSPGSSQ,QSSPGSSQLV,IQSSPGSSQL,SPG LUAD S R527S]SPGSSQLVHIPEETQENISTSPKS SSQLVHI SS LRBA c.6307G>A p.E210 VSLSTPAQLVAPSVVVKGTLSVTSS[p.E LSVTSSKLY,TLSVTSSKL,GTLSVTSSK,TSSKLYFEV,SVTSSKLY UCEC 3K 2103K]KLYFEVDEEDPNFKKIDPKILAYT F,VTSSKLYFEV,KGTLSVTSSK,TLSVTSSKLY,LSVTSSKLYF EG LRCH2 c.2150A>G p.D717 SIHVPSPAVPKLSMAKCRRNVENFL[p.D FLGACKKLGV KIRC G 717G]GACKKLGVSQERLCLPHHILEER GLV LRFN5 c.396C>A p.N132 NSNRLTKITNDMFSGLSNLHHLILN[p.N ILNKNQLTL,NLHHLILNK,ILNKNQLTLI,SNLHHLILNK,LILNK LUAD K 132K]KNQLTLISSTAFDDVFALEELDLSY NQLTL N   LRIG1 c.70C>G p.L24V MARPVRGGLGAPRRSPCLLLLWL[p.L2 LLLLWLVLL,LLWLVLLRL,LVLLRLEPV,LLLWLVLLR,LLLWLV ACC 4V]VLLRLEPVTAAAGPRAPCAAACTCAG LLRL,WLVLLRLEPV,SPCLLLLWLV LRIG1 c.76C>G p.L26V MARPVRGGLGAPRRSPCLLLLWLLL[p.L LLLLWLLLV,LLWLLLVRL,LLLVRLEPV,VRLEPVTAA,CLLLLW ACC 26V]VRLEPVTAAAGPRAPCAAACTCA LLLV,LLLWLLLVRL,WLLLVRLEPV GDS   LRP1 c.3172C>A p.P105 TCDGDNDCGDYSDETHANCTNQATR[p. ATRTPGGCH,ATRTPGGCHT,TPGGCHTDEF KIRP,PRAD 8T P1058T]TPGGCHTDEFQCRLDGLCIP   LRWRCD   LRP1 c.4462_446 p.G148 GSGHMEVLRGHEFLSHPFAVTLYGG[p. TLYGGGGLL STAD 3insG 8fs G1488fs]GGLLD* LRP1 c.4462de|G p.G148 GSGHMEVLRGHEFLSHPFAVTLYGG[p. WLRPTSGPA,PVRPMGARA,FAVTLYGGR,PATMSPWYR, STAD 8fs G1488fs]RSTGLTGEQTHWLRPTSGPA TTPPASPWL,TTGPCPAPA,RPTSGPATM,PPASPWLPI,RPM TMSPWYRGPTPSPLTCRCTTPPASPWL GARAPA,YRGPTPSPL,CTTPPASPW,WLPIPVRPM,GPATM PIPVRPMGARAPAPTCVSSTTTGPCPA SPWY,TLYGGRSTGL,GLTGEQTHWL,TMSPWYRGPT,WYR PAPTS* GPTPSPL,HWLRPTSGPA,GARAPAPTCV,SGPATMSPWY,P FAVTLYGGR,LTGEQTHWLR,CTTPPASPWL,TTTGPCPAPA, SPWYRGPTPS,TPPASPWLPI,LPIPVRPMGA,IPVRPMGAR A,RPMGARAPAP,APAPTCVSST,WLRPTSGPAT,LRPTSGP ATM,TSGPATMSPW,RCTTPPASPW,GEQTHWLRPT LRP10 c.15_17de| p.L11d MLLATLLLLL[p.L11de|]GGALAHPDRII TLLLLLGGA PRAD CCT e| FPNHACEDPPAVLLEVQ LRP11 c.275C>G p.P92R QQERPQEELELELRAGGGPQEDCPG[p. RGSGGYSAM,CPGRGSGGY,GRGSGGYSAM ACC P92R]RGSGGYSAMPDAIIRTKDSLAAG ASF LRP12 c.928G>T p.G310 CTWLIDTGDHRKVILRFTDFKLDGT[p.G GTCYGDYVK,KLDGTCYGDY,TDFKLDGTCY,TCYGDYVKIY TGCT C 310C]CYGDYVKIYDGLEENPHKLLRVLT AF LRP1B c.10687G>T p.G356 FDCADGSDERNCETSCSKDQFRCSN[p. CSNCQCIPAK LUAD 3C G3563C]CQCIPAKWKCDGHEDCKYGE DEKSCE LRP1B c.4174C>T p.L139 SLRTTLIAGAMEHPRAIALDPRYGI[p.L1 RYGIFFWTD,ALDPRYGIF,YGIFFWTDW,DPRYGIFFW,GIFF UCS 2F 392F]FFWTDWDANFPRIESASMSGAG WTDWDA,IALDPRYGIF,RYGIFFWTDW,FFWTDWDANF,A RKTI LDPRYGIFF LRP2 c.12117G> p.M40 FGTCPQHCRNTKGSYECVCADGFTS[p. TSISDRPGK,DGFTSISDR,SISDRPGKR,FTSISDRPGK,TSISD LUAD C 39I M4039I]ISDRPGKRCAAEGSSPLLLLPD RPGKR NVRI LRP2 c.1547C>T p.A516 IDMVNLDGSYRVTLITENLGHPRGI[p.A IVVDPTVGY,LGHPRGIVV,VVDPTVGYLF,IVVDPTVGYL,GI LUSC V 516V]VVDPTVGYLFFSDWESLSGEPKL VVDPTVGY,HPRGIWVVDPT ERA LRP2 c.2210C>T p.S737 IFSSQVAIRGIPFTLSTQEDVMVPV[p.S7 VLGNPSFFV,VPVLGNPSF,QEDVMVPVL,VPVLGNPSFF,M CRC L 37L]LGNPSFFVGIDFDAQDSTIFFSDMS VPVLGNPSF,TQEDVMVPVL K LRP2 c.7295G>T p.R243 NHSPPFQTINVERTVMSLDYDSVSD[p. SVSDIIYFT,IIYFTQNLA,DIIYFTANL,LDYDSVSDI,YDSVSDI UCEC 2I R2432I]IIYFTQNLASGVGQISYATLSSGI IY,DSVSDIIYFT,DIIYFTQNLA,LDYDSVSDII,YDSVSDIIYF, HT SDIIYFTQNL LRP2 c.9127C>T p.R304 CGDYSDERGCLYQTCQQNQFTCQNG[p. CQNGCCISK CRC 3C R3043C]CCISKTFVCDEDNDCGDGS DELMHLC LRP5 c.4825T>C p.S160 LSAEDSCPPSPATERSYFHLFPPPP[p.S1 HLFPPPPPPC PRAD 9P 609P]PPCTDSS* LRP6 c.2024G>A p.R675 NNNNVAIPLTGVKEASALDFDVTDN[p. FDVTDNQIY,QIYWTDISL,NQIYWTDISL,QIYWTDISLK CRC Q R675Q]QIYWTDISLKTISRAFMNGSALE HVV LRRC1 c.679G>A p.D227 LDHRDLIPIIAALEYNQWFTKLSSK[p.D2 KLSSKNLKL,FTKLSSKNLK,TKLSSKNLKL BLCA 6A N 27N]NLKLSTDVCEQILRVVSRSNRLEELV LRRC1 c.2359C>T p.R787 AVDKELQVILESMVSLTQELCPVAM[p. ELCPVAMWV,WVAEGHNKM,QELCPVAMW,AMWVAEG PRAD 6B W R787W]WVAEGHNKMLSNVAERVTVP HNK,MWVAEGHNKM,ELCPVAMWVA,WVAEGHNKML, RNFIRG QELCPVAMWV LRRC1 c.652C>T p.R218 RRLENLYVVEEKDLCAACLRKCQNA[p. NAWDNLNRI,CLRKCQNAW,RKCQNAWDNL CRC 8 W R218W]WDNLNRIKNMATTTPRKTIFP NLISP LRRC3 c.68A>C p.K23T RKKTSSEGETKPQTSTVNKFLR[p.K23T] FLRASNAES,RASNAESRK,STVNKFLRA,FLRASNAESR CRC 1 ASNAESRKEDNDLKTSDSQPSDWIQK LRRC3 c.305C>G p.T102 ELEQPHTQQGPEKLAGNAIYTKPSF[p.T FSQEHKAAV,SQEHKAAVSV PRAD 7A2 S 102S]SQEHKAAVSVLTPFSKGAPSTSSP AK LRRC3 c.1217C>A p.A406 ETPGQPPEHHEVTVSPPGHHQTHHL[p. HLDSPSVSV,HLDSPSVSVK,QTHHLDSPSV,HQTHHLDSPS CESC 7A3 D A406D]DSPSVSVKPPDVQLTIAAEPSAE VGT LRRC4 c.1674de|C p.D558 KEPAKEWKVLKKKKEPPKELRQDPP[p. SSRCWAGAW,ELRQDPPSSR,RQDPPSSRCW STAD 3 fs D558fs]SSRCWAGAW* LRRC7 c.4166G>A p.R138 VPPDTITKKAGSHIQTLMGSQSLQH[p. HSREQQPYE,SQSLQHHSR,HHSREQQPY,LMGSQSLQHH, CRC 9H R1389H]HSREQQPYEGNINKVTIQQFQ QHHSREQQPY SPLPI LRRCC c.17C>T p.A6V MEAAA[p.A6V]VVVAAEAEVENEDGD VVVAAEAEV,EAAAVVVAA,MEAAAVVVA,AVVVAAEAEV, TGCT 1 SSCGDVCFMDK MEAAAVVVAA LRRIQ c.2375G>T p.W79 RKRPVKCPANMTPALDKLEILRCGP[p. LEILRCGPL,GPLDTLQQV,ILRCGPLDTL LUAD 1 2L W792L]LDTLQQVTTVTFQDLPGCVLST LAEC LRRIQ c.732_733i p.K244f LIVQRWIRGFLVRKNLSPVFFHKKK[p.K KKKTAGKNY,FFHKKKTAGK,HKKKTAGKNY PRAD 3 nsA s 244fs]TAGKNY* LRRT c.728C>A p.S243 SKINFAHFPRLFNLRSIYLQWNRIR[p.S2 LQWNRIRYI,RIRYISQGL,YISQGLTWT,RYISQGLTW,YLQW LUAD M4 Y 43Y]YISQGLTWTWSSLHNLDLSGNDIQ NRIRY,LQWNRIRYI,IYLQWNRIRY,YISQGLTWTW,RIRYIS GI QGLT,LQWNRIRYIS,NRIRYISQGL,IRYISQGLTW LRTM c.416C>T p.S139 DLTNLTELQLRNNSIRTLDRDLLRH[p.S1 LLRHLPLLR,LPLLRHLDL,DLLRHLPLL,RDLLRHLPL,RHLPLLR BLCA 2 L 39L]LPLLRHLDLSINGLAQLPPGLFDGLL HL,DLLRHLPLLR,RDLLRHLPLL,LRHLPLLRHL LRTM c.526C>G p.L176 GLAQLPPGLFDGLLALRSLSLRSNR[p.L1 SLSLRSNRV,VQNLDRLTF,LRSNRVQNL,SLRSNRVQNL,RS CESC 2 V 76V]VQNLDRLTFEPLANLQLLQVGDNP NRVQNLDR,RVQNLDRLTF,RSLSLRSNRV WE LSG1 c.1550G>T p.R517 ITPREDEDPHRPPTSEELLTAYGYM[p.R LLTAYGYML,TAYGYMLGF,AYGYMLGFM,GYMLGFMTA,Y LUSC L 517L]LGFMTAHGQPDQPRSARYILKDY MLGFMTAH,LTAYGYMLGF,YMLGFMTAHG,TAYGYMLGF VSG M,YGYMLGFMTA LTA4H c.319T>C p.F107 YKGSPMEISLPIALSKNQEIVIEIS[p.F10 EISLETSPK,QEIVIEISL,LETSPKSSA,NQEIVIEISL,LET KIRC L 7L]LETSPKSSALQWLTPEQTSGKEHPYL SPKSSAL LTB4R c.217T>C p.F73L QKRSVTALMVLNLALADLAVLLTAP[p.F VLLTAPLFL,LTAPLFLFIF,LAVLLTAPL,TAPLFLHFL,AVLLTAP TGCT 73L]LFLHFLAQGTWSFGLAGCRLCHYV LF,LTAPLFLHFL,DLAVLLTAPL,LLTAPLFLHF,TAPLFLHFLA,L CG AVLLTAPLF LUC7L c.442T>A p.S148 GKNEEKIQVLTDKIDVLLQQIEELG[p.S1 IEELGTEGKV TGCT 3 T 48T]TEGKVEEAQGMMKLVEQLKEERE LLR LUM c.929G>T p.R310 QLEKFDIKSFCKILGPLSYSKIKHL[p.R31 SYSKIKHLL,YSKIKHLLL,SYSKIKHLLL,LSYSKIKHLL LUSC L 0L]LLDGNRISETSLPPDMYECLRVANEV LUM c.988C>T p.R330 KIKHLRLDGNRISETSLPPDMYECL[p.R3 DMYECLCVA,YECLCVANEV GBM C 30C]CVANEVTLN* LY9 c.205A>C p.I69L RASGKDSAPTVVSGILGGSVTLPLN[p.I6 VTLPLNLSV,SVTLPLNLSV BRCA 9L]LSVDTEIENVIWIGPKNALAFARPKE LYPD4 c.191C>A p.T64K AVAFHNWKWLLMRNMVCKLQEGCEE EEKLVFIET,KLQEGCEEKL,KLVFIETGTA,QEGCEEKLVF,CEE TGCT [p.T64K]KLVFIETGTARGVVGFKGCSSS KLVFIET SSYP LYST c.2130G>T p.Q710 DLLWKWDALKAYQNFVFEEDRLHSI[p. HIANHICNL,HSIFHIANHI,EEDRLHSIH,HIANHICNL,RLHSIH KIRC H Q710H]HIANHICNLIQKGNIVVQWKLY IANH,FEEDRLHSIH,IHIANHICNL,EEDRLHSIHI NYIF LZTS1 c.1294_134 p.RTQD AKASEILGLKAQLKDTRGKLEGLEL[p.RT KLEGLELEV,GKLEGLELEV PAAD 1de|AGGAC LEGALR QDLEGALRTKGLEL432de|]EVCENELQ CCAGGACC TKGLEL RKKNEAELLREKVNLLEQELQELRAQAA TGGAGGGC 432de| LARDMGPPTFPEDVPALQRELERLRAEL GCCCTGCG REERQGHDQ CACCAAGG GCCTGGAG CTG LZTS2 c.298de|C p.P100f VPPRKAVPVTSFTYINEDFRTESPP[p.P1 SSLSLESWR,HTMPTSAAH,SWRRTWRRS,ESWRRTWRR,E CRC s 00fs]AQAVMLRMPESSGHTMPTSAAH SSGHTMPT,SPPAQAVML,MPESSGHTM,AAHHQSSSL,TE HQSSSLSLESWRRTWRRS* SPPAQAV,HHQSSSLSL,SSSLSLESW,SLESWRRTW,RMPES SGHTM,SSSLSLESWR,SSLSLESWRR,MLRMPESSGH,HTM PTSAAHH,SLESWRRTWR,SAAHHQSSSL,TESPPAQAVM,A HHQSSSLSL,HQSSSLSLES,QSSSLSLESW,LSLESWRRTW,M PTSAAHHQS MAEL c.1033C>T p.R345 EAHVPLQDYEASNSVTPKMVVLDAG[p. VLDAGCYQK,MVVLDAGCY,DAGCYQKLR,VLDAGCYQKL, CRC C R345C]CYQKLRVGSSGFSHFNSSNEEQ VVLDAGCYQK,KMVVLDAGCY RSNT MAF c.158de|G p.G53fs MKFEVKKEPVETDRIISQCGRLIAG[p.G CGRLIAGAR,SQCGRLIAGA,RLIAGARCPP CLL 53fs]ARCPPPP* MAGE c.1826T>A p.L609 PQGEDSLSPHYFPQSPPQGEDSMSP[p. GEDSMSPHY,SMSPHYFPQ,SMSPHYFPQS,QGEDSMSPHY, CLL C1 H L609H]HYFPQSPLQGEEFQSSLQSPVSI SPHYFPQSPL,GEDSMSPHYF CSS MAGE c.714_716d p.P239 FQSSPERTQSTFEGFAQSPLQIPVS[p.P IPVSSSSST,VSSSSSTLL,IPVSSSSSTL KIRC C1 e|CCC de| 239de|]SSSSTLLSLFQSFSERTQSTFEGF AQSS MAGE c.1138G>A p.V380 SVLPIPGEGLSTSVPPTASDGSDTS[p.V3 ASDGSDTSM,SMPPTPGEGA,TASDGSDTSM CRC E1 M 80M]MPPTPGEGASTLVQPTAPDGPGS SVL MAGE c.133de|C p.Q45f GDGRGEIQATNASGSPTSMLVVDAP[p. MLVVDAPSA,LVVDAPSAL,TLSVSTLPR,VVDAPSALR,VSTL STAD E2 s Q45fs]SALRRQSTLSVSTLPRPFRTRMT PRPFR,TLPRPFRTR,PFRTRMTWR,SALRRQSTL,LPRPFRTR WRS* M,RPFRTRMTW,LRRQSTLSV,RQSTLSVST,QSTLSVSTL,SV STLPRPF,SMLVVDAPSA,MLVVDAPSAL,ALRRQSTLSV,RQ STLSVSTL,STLSVSTLPR,LVVDAPSALR,VVDAPSALRR,SVST LPRPFR,STLPRPFRTR,RPFRTRMTWR,APSALRRQST,LPRP FRTRMT,LSVSTLPRPF,RRQSTLSVST MAGI c.3467G>T p.G115 KGFGFSLRGGREYNMDLYVLRLAED[p. YVLRLAEDV,VPAERCGKM,RLAEDVPAER LUAD 1 6V G1156V]VPAERCGKMRIGDEILEINGET TKNM MAGI c.3592C>T p.R119 INGETTKNMKHSRAIELIKNGGRRV[p.R GGRRVCLFL,GRRVCLFLK,GGRRVCLFLK,IKNGGRRVCL,KN CRC 1 8C 1198C]CLFLKRGDGSVPEYDPSSDRHG GGRRVCLF PATG MAGI c.1348C>A p.L450 LSTTLKKSNMGFGFTIIGGDEPDEF[p.L4 EFMQVKSVI,MQVKSVIPD,DEFMQVKSV,MQVKSVIPDG, UCEC 2 M 50M]MQVKSVIPDGPAAQDGKMETG DEFMQVKSVI DVIVY MAGI c.3130C>A p.P104 PSSEKQSPMAQQSPLAQQSPLAQPS[p. STATPNSPI,STATPNSPIA,SPLAQPSTAT,QQSPLAQPST LUAD 2 4T P1044T]TATPNSPIAQPAPPQPLQLQG HENSY MAM c.1771C>A p.Q591 QANQQMPSVLPSQNKPSLLHYTQQQ[p. LLHYTQQQK,SLLHYTQQQI KIRP L2 K Q591K]KQQQQQQQQQQQQQQQ QQQQQQQQQQ MAM c.1715A>T p.Q572 YLQQPTPTQASSATASSTATATLQL[p.Q STATATLQLL TGCT,UCS LD1 L 572L]LQQQQQQQQQPDHSSFLLQQM MQQPQ MAM c.484_485i p.P162f QPHPRMKPSPLTPCPPGVPSPSPPP[p. SPSPPPTQV STAD STR nsC s P162fs]TQVGTSDP* MAN1 c.1291_129 p.G431 MEAKNMYYEALEAIETYLLNVSPGG[p.G4 LLNVSPGGA,RGHDRPWRR,VSRVIRPLR,DGAPGLFLR,DVSRV STAD C1 2insG fs 31fs]ADLHCRVARGDSGPQDGAPGLFLR IRPL,GPQDGAPGL,RPWRRGCQG,RPLRHQTWA,FLRGH GHDRPWRRGCQGRKEGPLPRAR DRPW,YLLNVSPGGA,LFLRGHDRPW,QGRKEGPLPR,RARSPDH SPDHQDVSRVIRPLRHQTWA* QDV,VSRVIRPLRH,FLRGHDRPWR,DVSRVIRPLR,VIRPLRHQTW MAP1 c.6187de|C p.P206 GPTVPPRPEPGPSMEPSLTPPAVPP[p.P LTPPAVPPV,SLTPPAVPPV STAD A 3fs 2063fs]VLLS* MAP1 c.6138G>T p.E204 EGYSYETSTKTTRTPDTSTYCYETA[p.E2 ETADKITRT,STYCYETADK,TYCYETADKI CRC B 6D 046D]DKITRTPQASTYSYETSDLCYTAE KK MAP1 c.1232C>G p.S411 EKMGVGRLDMYVLHPPSAGAERTLA[p. RTLACVCAL,LACVCALL,AERTLACVC,RTLACVCALL,TLAC ACC S C S411C]CVCALLVWHPAGPGEKVVRVL VCALLV,LACVCALLVW,AERTLACVCA FPGCT MAP2 c.1590G>T p.K530 QAVTDSAMTSKTLEKAMTEPSALIE[p.K SALIENSSI,IENSSIQEL,IENSSIQELF CRC N 530N]NSSIQELFEMRVDDKDKIEGVGA ATS MAP2 c.4414_441 p.K147 EPSTVSRDEVRRKKAVYKKAELAKK[p.K SLQEIHFKT,LSLQEIHFK,KNRSSGPLS,HFKTCYQIY,KKNRSS STAD 5insA 2fs 1472fs]NRSSGPLSLQEIHFKTCYQIY* GPL,NRSSGPLSL,QEIHFKTCY,IHFKTCYQI,KNRSSGPLSL,IH FKTCYQIY,EIHFKTCYQI,AKKNRSSGPL,LQEIHFKTCY MAP2 c.171G>C p.K57N ALQKKLEELELDEQQRKRLEAFLTQ[p.K TQNQKVGEL,TQNQKVGELK,EAFLTQNQKV CLL K1 57N]NQKVGELKDDDFEKISELGAGNG GVV MAP2 c.171G>T p.K57N ALQKKLEELELDEQQRKRLEAFLTQ[p.K TQNQKVGEL,TQNQKVGELK,EAFLTQNQKV LUAD K1 57N]NQKVGELKDDDFEKISELGAGNG GVV MAP2 c.370C>T p.P124 IHLEIKPAIRNQIIRELQVLHECNS[p.P12 NSSYIVGFY,SYIVGFYGA,VLHECNSSY,HECNSSYIV,CNSSYI SKCM K1 S 4S]SYIVGFYGAFYSDGEISICMEHMDG VGF,CNSSYIVGFY,VLHECNSSYI,SYIVGFYGAF,SSYIVGFYG G A,QVLHECNSSY MAP2 c.551C>T p.S184 PYIVQFYGALFREGDCWICMELMST[p. MSTLFDKFY,STLFDKFYK,TLFDKFYKY,ELMSTLFDK,LMSTL BRCA K4 L S184L]LFDKFYKYVYSVLDDVIPEEILGKI FDKF,ICMELMSTL,CMELMSTLF,LMSTLFDKFY,STLFDKFY T KY,LFDKFYKYVY,TLFDKFYKYV,WICMELMSTL,MSTLFDKF YK,ICMELMSTLF,ELMSTLFDKF MAP2 c.752G>T p.5251I IHRDIKPSNILLDRSGNIKLCDFGI[p.S25 IIGQLVDSI,IKLCDFGII,GIIGQLVDSI BRCA K4 1I]IGQLVDSIAKTRDAGCRPYMAPERID MAP2 c.783_784d p.T261f DRSGNIKLCDFGISGQLVDSIAKTR[p.T2 SIAKTRCWL BRCA K4 e|AA s 61fs]CWL* MAP2 c.860G>A p.R287 RDAGCRPYMAPERIDPSASRQGYDV[p. DVHSDVWSL,RQGYDVHSDV,QGYDVHSDVW,YDVHSDV CRC K4 H R287H]HSDVWSLGITLYELATGRFPYPK WSL WNS MAP2 c.1334A>G p.Q445 VQFNDGNAAVVSMWVCRALEERRSQ[p. RALEERRSQR KIRC K5 R Q445R]RGPP* MAP3 c.2281_228 p.I761f LNCILGNQTESNNWQELLGRLCLID[p.I LIDCCWNFL,FLLNFILIL,FILILSVLM,VLMFHKLSL,LMFHKLS BRCA K1 4de|ATAG s 761fs]CCWNFLLNFILILSVLMFHKLSLL LL,KLSLLKSGI,ILSVLMFHK,MFHKLSLLK,CLIDCCWNF,CW KSGIRSCCPS* NFLLNFI,NFLLNFILI,ILILSVLMF,CCWNFLLNF,WNFLLNFIL, LSVLMFHKL,CLIDCCWNFL,LIDCCWNFLL,FLLNFILILS,LLN FILILSV,ILSVLMFHKL,VLMFHKLSLL,LILSVLMFHK,LMFHK LSLLK,CWNFLLNFIL,NFLLNFILIL,NFILILSVLM,SVLMFFIKL SL,LNFILILSVL,FILILSVLMF,HKLSLLKSGI MAP3 c.4036_403 p.V134 LFIEWMAGGSVAHLLSKYGAFKESV[p. SVINYTEQL,AFKESVINY,SVINYTEQLL,KYGAFKESVI,GAFK BRCA K1 8de|GTT 6de| V1346de|]INYTEQLLRGLSYLHENQIIH ESVINY,ESVINYTEQL RDVKGAN MAP3 c.4150_415 p.L138 LHENQIIHRDVKGANLLIDSTGQRL[p. WSCSQVGIK,RLKNCRFWS,GIKRNWCRR,VGIKRNWCR, BRCA K1 1insT 4fs L1384fs]KNCRFWSCSQVGIKRNWCRR GQRLKNCRF,CRFWSCSQV,SQVGIKRNW,LIDSTGQRLK, VSGTITGDNCIYGT* RFWSCSQVGI,RLKNCRFWSC,GIKRNWCRRV,GTITGDNCIY, STGQRLKNCR,QVGIKRNWCR,VGIKRNWCRR,GQRLKNCRFW MAP3 c.953_954i p.L318f DGFSPYSPEETNRRVNKVMRARLYL[p. VMRARLYLT,RLYLTAADR,RARLYLTAA,MRARLYLTA,VMR BRCA K1 nsA s L318fs]TAADRA* ARLYLTA,RLYLTAADRA,KVMRARLYLT,RARLYLTAAD,MR ARLYLTAA MAP3 c.971C>T p.P324 YSPEETNRRVNKVMRARLYLLQQIG[p. QQIGLNSFL,LYLLQQIGL,LQQIGLNSF,RLYLLQQIGL,QQIGL GBM K1 L P324L]LNSFLIGGDSPDNKYRVFIGPQN NSFLI,LLQQIGLNSF,LQQIGLNSFL CSC MAP3 c.1345_134 p.R449 KLHFEKIKSEGTCLHRLEEELVMRR[p.R449 LVMRREELR,ELVMRREEL,ELVMRREELR,MRREELRHAL,E STAD K12 7de|AGG de| de|]EELRHALDIREHYERKLERANNLY ELVMRREEL MELN MAP3 c.824G>A p.R275 ENTSGFWLNRSNELIWLELQAWHAG[p. LQAWHAGQT,QAWHAGQTI,GQTINDQDF,LQAWHAGQ CRC K4 Q R275Q]QTINDQDFFLYTARQAIPDIIN TI,QTINDQDFFL,GQTINDQDFF,LELQAWHAGQ EILT MAP3 c.1570G>C p.E524 AYLTLDHQLQPLAPCPNSKESMAVF[p. MAVFQQHCK,AVFQQHCKM,SMAVFQQHCK,QQHCKMA HNSC K7 Q E524Q]QQHCKMAQEYMKVQTEIALLL QEY,MAVFQQHCKM,KESMAVFQQH QRKQE MAP4 c.1021C>G p.R341 SRGQHGPAERTPSEIQFHQVKFGAP[p. QVKFGAPGR,HQVKFGAPG,QVKFGAPGRK,HQVKFGAPG TGCT K2 G R341G]GRKETDPLNEPWEEEWTLLGK R,APGRKETDPL EELSG MAP4 c.1970de|C p.P657f LFDYARQMQKLPVAIPAHKLPDRIL[p.P RILQGNFLY,FLYQQKSLK,KSLKPNGAR,KPNGARSVV,YQQ HNSC K3 s 657fs]QGNFLYQQKSLKPNGARSVVL* KSLKPN,SLKPNGARSV,NFLYQQKSLK,KPNGARSVVL,GNF LYQQKSL,YQQKSLKPNG,LPDRILQGNF MAP7 c.239_240i p.A80fs ATSSKQLPLEPESPSGQVGPRPAPP[p.A RPAPPAGRV,APPAGRVPF,PPAGRVPFL,RPAPPAGRVP,AP STAD D1 nsC 80fs]AGRVPFL* PAGRVPFL MAP7 c.1459C>T p.R487 ERLEKEEQDRLEREELKRKAEEERL[p.R4 RKAEEERLCL,EERLCLEEEA CRC D2 C 87C]CLEEEARKQEEERKRQEEEKKKQE GE MAP7 c.922de|C p.Q308 PQTKVEESPLEKVETPPKASVDAPP[p.Q KASVDAPPR STAD D3 fs 308fs]R* MAP9 c.1455G>T p.K485 QKKAAKREEALASFEAWKAMKEKEA[p. AMKEKEANK,KEANKIAAK,KEKEANKIA,AMKEKEANKI,KA HNSC N K485N]NKIAAKKRLEEKNKKKTEEENA MKEKEANK,EANKIAAKKR,KEKEANKIAA ARKG MAPK c.964G>A p.E322 NPHKRIEVEQALAHPYLEQYYDPSD[p.E3 YYDPSDKPI,KPIAEAPFK,QYYDPSDKPI,SDKPIAEAPF,KPIA CESC,HNSC 1 K 22K]KPIAEAPFKFDMELDDLPKEKLKELI EAPFKF MAPK c.943G>A p.E315 ELDVDKRLTAAQALTHPFFEPFRDP[p.E KEETEAQQPF BRCA 13 K 315K]KEETEAQQPFDDSLEHEKLTVDE WKQ MAPK c.1533de|G p.Q511 PPRLPPEARPGRRMFSTSALQGAQG[p. TMCEPPYSL,PLSSLLHPL,LLHPLALPA,GLSATRHWA,SLHLA STAD 15 fs Q511fs]VPGLCLEATPKPTGLSATRHW LCSC,ALPALPGPL,GLCLEATPK,CSCPSPFPR,KFQGACPGL, ATCPCWRGTMCEPPYSLHLALCSCPSP RGTMCEPPY,HWATCPCWR,EPPYSLHLA,TPKPTGLSA,PP FPRPLSSLLHPLALPALPGPLKFQGACPG YSLHLAL,CPSPFPRPL,SPFPRPLSS,FPRPLSSLL,APLTSSNKV, LLGGADEGPAPAPLTSSNKVMSAPN SSLLHPLAL,ALCSCPSPF,LQGAQGVPG,AQGVPGLCL,RH WATCPCW,LKFQGACPG,FQGACPGLL,DEGPAPAPL,CEPP YSLHL,GTMCEPPYSL,SLLHPLALPA,LLHPLALPAL,GLSATR HWAT,ALPALPGPLK,PFPRPLSSLL,KFQGACPGLL,ATRHW ATCPC,TSALQGAQGV,TPKPTGLSAT,EPPYSLHLAL,SPFPR PLSSL,FPRPLSSLLH,RPLSSLLHPL,LPALPGPLKF,APLTSSNK VM,LALCSCPSPF,LQGAQGVPGL,LEATPKPTGL,WRGTMC EPPY,LSSLLHPLAL,LALPALPGPL,LKFQGACPGL,CEPPYSLH LA MAPK c.298G>A p.V100 DNIVKVYEVLGPKGTDLQGELFKFS[p.V LFKFSMAYI,ELFKFSMAY,SMAYIVQEY,MAYIVQEYM,FKFS BRCA 4 M 100M]MAYIVQEYMETDLARLLEQGTL MAYIV,GELFKFSMA,FSMAYIVQEY,ELFKFSMAYI,SMAYIV AEEH QEYM,LQGELFKFSM,GELFKFSMAY,FKFSMAYIVQ MAPK c.1502C>A p.A501 KAALKAALLKSLRSRLRDGPSAPLE[p.A5 LEDPEPRKPV KIRP,TGCT 7 D 01D]DPEPRKPVTAQERQREREEKRRRR QE MAPK c.651_652i p.L217f SSSPLKTGEQTPPHEHICLSDELPP[p.L2 RVVPLLPRL,LLPRLGVGA,RLGVGATRI,RWHLRVVPL,RAAP CRC 8IP1 nsCC s 17fs]PRAAPPPPQIEAPPPTALAAAAQP PPPQI,AQPPRWHLR,LAAAAQPPR,EAPPPTALA,APPPTAL PRWHLRVVPLLPRLGVGATRIETESTTR AA,PPRWHLRVV,VPLLPRLGV,LPRLGVGAT,IEAPPPTAL,A PMCD* AQPPRWHL,WHLRVVPLL,DELPPPRAA,ETESTTRPM,QPP RWHLRV,ALAAAAQPPR,HLRVVPLLPR,AAQPPRWHLR,R WHLRVVPLL,CLSDELPPPR,EAPPPTALAA,APPPTALAAA,I EAPPPTALA,LAAAAQPPRW,AAAQPPRWHL,LRVVPLLPRL, IETESTTRPM,DELPPPRAAP,QPPRWHLRVV MAPK c.640_641i p.T214f ENLLYTSKRPNAILKLTDFGFAKET[p.T2 QLFDHSLLY,LLYTVLCGS,QPQLFDHSL,AKETHQPQL,KETH KIRC APK2 nsC s 14fs]HQPQLFDHSLLYTVLCGSRSAGSR QPQLF,FDHSLLYTV,QLFDHSLLYT,GSRSAGSREV,PQLFDH EV* SLLY,LLYTVLCGSR,YTVLCGSRSA,QPQLFDHSLL,FAKETHQ PQL,AKETHQPQLF,HQPQLFDHSL,FDHSLLYTVL 11- c.578G>T p.R193 PICKICFQGAEQGELLNPCRCDGSV[p.R VLYTHQLCL,LYTHQLCLL,GSVLYTHQL,VLYTHQLCLL,NPCR LUAD Mar L 193L]LYTHQLCLLKWISERGSWTCELCC CDGSVL YR 5-Mar c.508C>T p.R170 GLPTIPVMLILGKMIRWEDYVLRLW[p. RLWCKYSNK,LWCKYSNKL,YVLRLWCKY,DYVLRLWCIK,CK BRCA C R170C]CKYSNKLQILNSIFPGIGCPVPRI YSNKLQI,RLWCKYSNKL,CKYSNKLQIL PA MARC c.454de|A p.K152f ASSTSSPKAEDGATPSPSNETPKKK[p.K KKRSAFPSR,RSAFPSRSL,SAFPSRSLS,TPKKKRSAF,KKKRSA KIRC KS s 152fs]RSAFPSRSLSS* FPSR,RSAFPSRSLS,KRSAFPSRSL,SAFPSRSLSS MARS c.1442G>A p.R481 LPKQVADHYDNFRIYKALEAVSSCV[p.R SCVQQTNGF,VQQTNGFVQ,SSCVQQTNGF,QQTNGFVQR HNSC 2 Q 481Q]QQTNGFVQRHAPWKLNWESP H VDAPWL MAS1 c.970A>G p.R324 ISLFLIINSSANPIIYFFVGSLRKK[p.R324 GLKESLRVI,GSLRKKGLK,RKKGLKESL,GLKESLRVIL,VGSLR PRAD,THCA L G G]GLKESLRVILQRALADKPEVGRNKKA KKGLK MAT2 c.497A>G p.E166 YATDETEECMPLTIVLAHKLNAKLA[p.E KLNAKLAGL,KLNAKLAGLR,LAGLRRNGTL,GLRRNGTLPW, TGCT A G 166G]GLRRNGTLPWLRPDSKTQVTVQ HKLNAKLAGL YMQD MAX c.106A>T p.R36 SDEEQPRFQSAADKRAHHNALERKR[p. RWDHIKDSF,KRWDHIKDSF MM W R36W]WDHIKDSFHSLRDSVPSLQGEK ASRA MAX c.83A>G p.H28R DNDDIEVESDEEQPRFQSAADKRAH[p. RAHRNALER,SAADKRAHR,AHRNALERK,DKRAHRNAL,RA UCEC H28R]RNALERKRRDHIKDSFHSLRDSV HRNALERK,QSAADKRAHR PSL MB21 c.931C>G p.Q311 EWRLSFARSEVQLKKCISSSLMQAY[p.Q3 SLMQAYEAC,MQAYEACKA,LMQAYEACK,QAYEACKAI, HNSC,LUSC D2 E 11E]EACKAIIIKLLSRPKAISPYHLRS YEACKAIII,LMQAYEACKA,MQAYEACKAI,SLMQAYEACK,EA MM CKAIIIKL,QAYEACKAII MBD6 c.2194de|C p.P732f SVTTATTDPGASSLGKAPSNSGRPP[p.P SLALCWVPA,SGRPPNSLA,VPACWVTCL,PPNSLALCW,SLA STAD s 732fs]NSLALCWVPACWVTCLH* LCWVPAC,ALCWVPACWV,SGRPPNSLAL,NSLALCWVPA, WVPACWVTCL,RPPNSLALCW,LALCWVPACW MBD6 c.2338_233 p.G780 LPSLLQPPGPLLSGQLGLQLLPGGG[p.G SSSTPLRGF,LLPGGGSSST,LQLLPGGGSS,GSSSTPLRGF STAD 9insG fs 780fs]SSSTPLRGF* MBOA c.128G>A p.R43Q AVQLPIDQVNFVVCQLFALLAAIWF[p. LAAIWFQTY,LLAAIWFQT,AIWFQTYLFI,AAIWFQTYL,FQT CRC,UCEC T2 R43Q]QTYLHSSKTSSFIRHVVATLLGLYL YLHSSK,LLAAIWFQTY,ALLAAIWFQT,WFQTYLHSSK,LAAI A WFQTYL,FQTYLHSSKT MBOA c.1270C>T p.R424 HWFLKMRAYDYMCMGFVLLSLADTL[p. LSLADTLWY,SLADTLWYW,TLWYWASIY,LWYWASIYF,W HNSC T7 W R424W]WYWASIYFCIHFLALAALGL YWASIYFC,DTLWYWASI,LLSLADTLW,LLSLADTLWY,SLAD GLALGG TLWYWA,LSLADTLWYW,TLWYWASIYF,WYWASIYFCI,DT LWYWASIY,VLLSLADTLW,ADTLWYWASI MC5R c.325G>A p.A109 LVSMSSAWETITIYLLNNKHLVIAD[p.A HLVIADTFV,LVIADTFVR,KHLVIADTF,TFVRHIDNV,VIADT UCEC T 109T]TFVRHIDNVFDSMICISVVASMC FVRHI,TFVRHIDNVF,HLVIADTFVR,DTFVRHIDNV,NKHLVI SLL ADTF MCF2 c.2777G>A p.R926 KTMKLMTLSIRQLGRGSHRKFEIAS[p.R ASQNGLEKY,IASQNGLEK,FEIASQNGL,SQNGLEKYI,IASQ CRC L2 Q 926Q]QNGLEKYILQAASKEIRDCWFSEI NGLEKY,RKFEIASQNG,SQNGLEKYIL SK MCHR c.917C>T p.S306 QFFLAFALPFVVITAAYVRILQRMT[p.S3 ILQRMTFSV,RMTFSVAPA,RILQRMTFS,LQRMTFSVA,MT LUSC 1 F 06F]FSVAPASQRSIRLRTKRVTRTAIAIC FSVAPAS,VRILQRMTF,RILQRMTFSV,ILQRMTFSVA,TFSV APASQR,YVRILQRMTF,LQRMTFSVAP,QRMTFSVAPA,R MTFSVAPAS MCOL c.421G>A p.V141I VYTQSDVYDQLIFAVNQYLQLYNVS[p. YLQLYNVSI,NVSIGNHAY,LQLYNVSIG,SIGNHAYENK,QYL GBM N3 V141I]IGNHAYENKGTKQSAMAICQHF QLYNVSI,YNVSIGNHAY YKRG MECO c.2744G>A p.R915 SELLQSVPSMFNFRAPPNALPENLL[p.R LLQKGKERY,NALPENLLQK PRAD M Q 915Q]QKGKERYTCRYCGKIFPRSANLT RHL MECO c.2905C>T p.R969 TGEQPYRCKYCDRSFSISSNLQRHV[p.R NLQRHVCNI,RHVCNIHNK,LQRHVCNIH,HVCNIHNKEK,C CRC M C 969C]CNIHNKEKPFKCHLCDRCFGQQT NIHNKEKPF NLD MED1 c.107T>G p.L36R HRPLKRPRLGPPDVYPQDPKQKEDE[p. QKEDERTAL,KQKEDERTAL,RTALNVKQGF,KEDERTALNV CLL 2 L36R]RTALNVKQGFNNQPAVSGDEHG SAKN MED1 c.130G>A p.G44S LGPPDVYPQDPKQKEDELTALNVKQ[p. KQSFNNQPA,TALNVKQSF,QSFNNQPAV,KQSFNNQPAV, CLL 2 G44S]SFNNQPAVSGDEHGSAKNVSFN LTALNVKQSF,VKQSFNNQPA PAKI MED1 c.3670C>T p.L122 IRSSCDRHLLAASQNRIVDGAVFAV[p.L AVFAVFKAV,FAVFKAVFV,AVFKAVFVL,VFAVFKAVF,VDG PRAD 2 4F 1224F]FKAVFVLGDAELKGSGFTVTGG AVFAVF,FAVFKAVFVL,AVFAVFKAVF,IVDGAVFAVF TEEL MED1 c.3875G>A p.C129 LCTDKELILDPVLSNMQAQKLLQLI[p.C QLIYYPHGI,LIYYPHGIK,AQKLLQLIY,QKLLQLIYY,QAQKLL TGCT 2L 2Y 1292Y]YYPHGIKECTEGDNLQRQHIKRI QLIY,LQLIYYPHGI,QLIYYPHGIK,AQKLLQLIYY LQN MED1 c.6211C>T p.P207 QDPMRPRQPQVRQQQRLLQMQQPQ LQMQQPQQS,MQQPQQSQP,LQMQQPQQSQ,MQQPQ KIRC 2L 1S Q[p.P2071S]SQPQQPPQPQQSSQSQS QSQPQ QTLGLQAMQ MED1 c.6331_633 p.Q211 LGLQAMQPQQPLFPRQGLQQTQQQQ QQTQQQQTA,TQQQQTAAL,TQQQQTAALV,LQQTQQQ PRAD 2L 3de|CAG 5de| [p.Q2115de|]TAALVRQLQKQLSSNQP QTA,QQTQQQQTAA QQGVTPYGHPS MED1 c.104G>T p.S35I WRSTAFRQKLVSQIEDAMRKAGVAH[p. GVAHIKSSK,MRKAGVAHI,AHIKSSKDM,AMRKAGVAHI,M THCA 5 S35I]IKSSKDMESHVFLKAKTRDEYLSL RKAGVAHIK,AGVAHIKSSK VA MED1 c.1347C>G p.H449 TAGPAVHLKAMQLSWTSLALVGIDS[p. DSQGKLSVLR,IDSQGKLSVL,SQGKLSVLRL KIRP 6 Q H449Q]QGKLSVLRLSPSMGHPLEVGLA LRHL MEF2 c.295C>T p.P99S EPHESRTNSDIVEALNKKEHRGCDS[p.P SSDPDTSYV,DSSDPDTSY,DSSDPDTSYV,CDSSDPDTSY KIRP A 99S]SDPDTSYVLTPHTEEKYKKINEEFD N MEF2 c.380G>A p.R127 DTSYVLTPHTEEKYKKINEEFDNMM[p. NMMQNHKIA,MMQNHKIAP,MQNHKIAPG,MQNHKIAP TGCT A Q R127Q]QNHKIAPGLPPQNFSMSVTVP GL,MMQNHKIAPG,EEFDNMMQNH VTSPN MEFV c.1130G>A p.R377 CPRCQDSHERKSPGSLSPQPLPQCK[p. KHHLKQVQL,HHLKQVQLL,HHLKQVQLLF,QPLPQCKHHL, BRCA H R377H]HHLKQVQLLFCEDHDEPICLICS CKHHLKQVQL,KHHLKQVQLL LSQ MEGF c.3158C>T p.S105 NPYATIKDPPVLIPKSSECGYVEMK[p.S1 YVEMKLPAR,LPARRDSPY,KLPARRDSPY,YVEMKLPARR,L UCEC 10 3L 053L]LPARRDSPYAEINNSTSANRNVYE PARRDSPYA,SECGYVEMKL VE MEGF c.1178A>G p.Y393 RTCIDVDDCADSPCCQQVCTNNPGG[p. CECGCYAGY,NPGGCECGCY THCA 6 C Y393C]CECGCYAGYRLSADGCGCEDV DECAS MEGF c.1746_174 p.A582 DTFGKNCSFSCSCQNGGTCDSVTGA[p. LPLPPGCQW,CDSVTGALPL KIRC 6 7insC fs A582fs]LPLPPGCQWN* MET c.3280C>T p.H109 VVIGPSSLIVHFNEVIGRGHFGCVY[p.H RGHFGCVYY,HFGCVYYGTL KIRP 4Y 1094Y]YGTLLDNDGKKIHCAVKSLNRIT DIG MET c.3749T>C p.M12 LARDMYDKEYYSVHNKTGAKLPVKW[p. KLPVKWTAL,VKWTALESL,TALESLQTQK,AKLPVKWTAL,L KIRP 50T M1250T]TALESLQTQKFTTKSDVWSF PVKWTALES GVLLWE METT c.157C>G p.Q53E VWPNRIHTTAEKYREYEAREQTDQT[p. REQTDQTEA BRCA L15 Q53E]EAQELHRSQDRDFETMAKLHIP VMVD METT c.599G>A p.R200 EIIYDFCMCNPPFFANQLEAKGVNS[p.R SQNPRRPPP,SQNPRRPPPS CRC L16 Q 200Q]QNPRRPPPSSVNTGGITEIMAEG GEL METT c.521G>A p.R174 EETFTDLLQTLEHLCSNHSVILLAC[p.R1 ILLACQIRY,LACQIRYER,VILLACQIRY,SVILLACQIR,LLACQI CRC L21A Q 74Q]QIRYERDNNFLAMLERQFTVRKV RYER HYD METT c.168C>A p.F56L DFKQQKLEQEAQKNWDLFYKRNSTN[p. FYKRNSTNL,KRNSTNLFK,YKRNSTNLF,LFYKRNSTNL,FYKR CRC L6 F56L]LFKDRHWTTREFEELRSCREFED NSTNLF,YKRNSTNLFK,LFKDRHWTTR QKL METT c.170A>T p.Y57F LYVNMTSGPGGPAAAAGGRKENHQW QWFVCNREK,NHQWFVCNR,GRKENHQWF,KENHQWFV CLL L9 [p.Y57F]FVCNREKLCESLQAVFVQSYLD C,HQWFVCNREK,ENHQWFVCNR QGTQ MEX3 c.1600C>A p.R534 IWTPFEPVNPLSGFGSDPSGNMKTQ[p. TQSRGSQPS,KTQSRGSQPS,TQSRGSQPST TGCT C S R534S]SRGSQPSTPRLSPTFPESIEHPLA RR MEX3 c.537_545d p.179_ IPGGSLGSVLLPAARFDAREAAAAA[p.1 EAAAAAGVL,REAAAAAGV,EAAAAAGVLY,REAAAAAGVL ACC C e|CGCGGC 182AA 79_182AAAA>A]GVLYGGDDAQGMM GGC AA>A AAMLSHAYGPGGCGAAAAALN MFF c.19_20AG> p.S7F MSKGTS[p.S7F]FDTSLGRVSRAAFPSP TSFDTSLGR,KGTSFDTSL,GTSFDTSLGR,TSFDTSLGRV,SKG TGCT TT TAAEMAEISRI TSFDTSL MFF c.484C>T p.R162 TTPQNEEIRAVGRLKRERSMSENAV[p. RSMSENAVC,SENAVCQNG,NAVCQNGQLV CRC C R162C]CQNGQLVRNDSLWHRSDSAPR NKISR MFGE c.508G>A p.D170 GASRLASHEYLKAFKVAYSLNGHEF[p.D SLNGFIEFNF,HEFNFIHDV,SLNGHEFNFI,YSLNGHEFNF,EF UCEC 8 N 170N]NFIHDVNKKHKEFVGNWNKNA NFIHDVNK,HEFNFIHDVN VHVNL MFSD c.839G>A p.R280 FEAWYIHEHVERHDFPAEWIPATFA[p. WIPATFAQA,AQAAFWNHV,QAAFWNHVL,IPATFAQAA, CRC 5 Q R280Q]QAAFWNHVLAVVAGVAAEAV ATFAQAAFW,FAQAAFWNHV,AQAAFWNHVL,WIPATFA ASWIGL QAA,QAAFWNHVLA,IPATFAQAAF,AEWIPATFAQ MGA c.7304G>A p.R243 WSDKLQKEAEAFAYYRRTHTANERR[p. HTANERRQR,NERRQRGEM,RQRGEMRDL,RQRGEMRDL OV 5Q R2435Q]QRGEMRDLFEKLKITLGLLHSS F KVSK MGAT c.1330A>C p.T444 STSLKTYQHFTLEKAYLREDFFWAF[p.T FFWAFPPAA,AFPPAAGDF,DFFWAFPPA,FPPAAGDFI,AFP GBM 4B P 444P]PPAAGDFIRFRFFQPLRLERFFFRS PAAGDFI,WAFPPAAGDF,PPAAGDFIRF,REDFFWAFPP,ED G FFWAFPPA MGAT c.1034C>T p.T345 LAQKNVIRFKPSLFQHMGYYSSYKG[p.T SSYKGMENK,SYKGMENKL,GYYSSYKGM,YSSYKGMENK,S PRAD 4C M 345M]MENKLKDDDFEEESFDIPDNPP YKGMENKLK,MGYYSSYKGM,SSYKGMENKL,MENKLKDD ASLY DF MGST c.304de|A p.K102f FATCLGLVYIYGRHLYFWGYSEAAK[p.K EAAKNGSPV,SEAAKNGSPV STAD 2 s 102fs]NGSPVSD* MGST c.429_430i p.G143 SIALLGLVGTTVCSAFQHLGWVKSG[p. GQWTQMLPL,GLKTLIHFK,QMLPLKNYR,GFGQWTQML, KIRC 3 nsT fs G143fs]FGQWTQMLPLKNYRGLKTLIH RGLKTLIHF,QWTQMLPLK,PLKNYRGLK,TQMLPLKNY, FK* LPLKNYRGL,HLGWVKSGF,WVKSGFGQW,SGFGQWTQM, KNYRGLKTL,WTQMLPLKNY,MLPLKNYRGL,GQWTQMLPLK, RGLKTLIHFK,TQMLPLKNYR,GWVKSGFGQW,QHLGWVKS GF,KSGFGQWTQM,SGFGQWTQML,FGQWTQMLPL,LKN YRGLKTL,KNYRGLKTLI,YRGLKTLIHF MICA c.952de|G p.G318 HPVPSGKVLVLQSHWQTFHVSAVAA[p. VSAVAALLF,AVAALLFLL,LLLLFSMSV,LLLFSMSVV,LLFSMS CESC fs G318fs]LLFLLLLFSMSVVVRRKHQLQR WV,HVSAVAALL,SMSVVVRRK,FSMSVVVRR,ALLFLLLLF, VQSS* LFLLLLFSM,VVRRKHQLQ,LFSMSVVVR,SAVAALLFL,VVVR RKHQL,FHVSAVAAL,VAALLFLLL,HQLQRVQSS,SAVAALLF LL,AVAALLFLLL,LLFLLLLFSM,FLLLLFSMSV,LLLLFSMSVV,L LLFSMSVVV,LLFSMSVVVR,FSMSVVVRRK,AALLFLLLLF,V VRRKHQLQR,HVSAVAALLF,LFSMSVVVRR,SVVVRRKHQL, FHVSAVAALL MIER2 c.391C>T p.L131 ESEGGDVAPNLPDMTLDKEQIAKDL[p. KEQIAKDLF TGCT F L131F]FSGEEEEETQSSADDLTPSVTSH EAS MKI67 c.3241C>A p.R108 REPAGDGKSIRTFKESPKQILDPAA[p.R AASVTGMKK,DPAASVTGM,SVTGMKKWPR,AASVTGMK LUAD 1S 1081S]SVTGMKKWPRTPKEEAQSLEDL KW AGFK MKI67 c.4991_499 p.T166 VGVKEELLAVGKLTQTSGETTHTHT[p.T HTKSQQEMV,HTHTKSQQEM,HTKSQQEMVR STAD 2insCA 4fs 1664fs]KSQQEMVRA* MKI67 c.4992_499 p.T166 VGVKEELLAVGKLTQTSGETTHTHT[p.T HTQSQQEMV,THTQSQQEM,HTHTQSQQEM,HTQSQQE UCEC 3insCA 4fs 1664fs]QSQQEMVRA* MVR MKI67 c.6637C>G p.H221 AQPLEDLAGLKELFQTPICTDKPTT[p.H CTDKPTTDEK CLL 3D 2213D]DEKTTKIACRSPQPDPVGTPTIF KPQ MKL1 c.920de|C p.P307f HHNYQAILPAPPKSAGEALGSSGTP[p.P PLGPVGWHV,QYAASPLPI,GWHVRTAPH,LGSSGTPQY,YA STAD s 307fs]QYAASPLPIAAPARAPLGPVGW ASPLPIA,IAAPARAPL,TPQYAASPL,SPLPIAAPA,LPIAAPAR HVRTAPH* A,ALGSSGTPQY,YAASPLPIAA,APARAPLGPV,PQYAASPLP I,ARAPLGPVGW,APLGPVGWHV MKLN c.1455C>A p.F485 CMLFHSKNRCLYVFGGQRSKTYLND[p. YLNDLFSYD,TYLNDLFSY,RSKTYLNDL,KTYLNDLFS,SKTYLN UCEC 1 L F485L]LFSYDVDSDHVDIISDGTKKDSG DLF,KTYLNDLFSY,YLNDLFSYDV,RSKTYLNDLF MVP MKRN c.1343C>A p.P448 PEGWGDEPPGPGGGSFSAYWHQLVE[p. YWHQLVEH,HVRMGEGNM,HQLVEHVRM,AYWHQLVE LUAD 3 H P448H]HVRMGEGNMLYKSIKKELVV HV,HVRMGEGNML,YWHQLVEHVR,SAYWHQLVEH,WH LRLASL QLVEHVRM MKRN c.809G>T p.G270 YYASRGVCFRGESCMYLHGDICDMC[p. CVLQTLHPM,CDMCVLQTL,MCVLQTLHPM LUSC 3 V G270V]VLQTLHPMDAAQREEHMRACI EAHEK MLL2 c.1939_194 p.P647f ASRLSPPPEDSPMSPPPEESPMSPP[p.P EESPMSPPT STAD 0insC s 647fs]T* MLL2 c.1940de|C p.P647f EASRLSPPPEDSPMSPPPEESPMSP[p.P RLHASPHHL,SLRSHAYAL,RLRDHICPL,SLGNHLCPL,RLRSR STAD s 647fs]HLRYRAYPPCLWCHACLHRLRN TCLL,GLRNRICPL,SLRSHPCPL,HLRSCPCSL,HLGSHPCRL,H LPCPHRLRSLPRPLHLRLHASPHHLRTPP LRTHLLPH,GLRSHTYLR,RTHLLPHHR,SQANALHLR,RYRAY HPHHLRTHLLPHHRRTRSCPCRWRSHP PPCL,HLRYRAYPP,RLRNLPCPH,RLRSLPRPL,RSLPRPLHL,H CCHYLRSRNSAPGPRGRTCHPGLRSRT LRLHASPH,HLRTPPHPH,RTPPHPHHL,RTRSCPCRW,RWR CPPGLRSHTYLRRLRSHTCPPSLRSHAY SHPCCH,RSHPCCHYL,HYLRSRNSA,RSRNSAPGP,RGRTCH ALCLRSHTCPPRLRDHICPLSLRNCTCPP PGL,RSRTCPPGL,RSHTYLRRL,HTYLRRLRS,RLRSHTCPP,RS RLRSRTCLLCLRSHACPPNLRNHTCPPSL HTCPPSL,RSHAYALCL,RSHTCPPRL,RSRTCLLCL,RSHACPP RSHACPPGLRNRICPLSLRSHPCPLGLKS NL,RNHTCPPSL,RSHACPPGL,RNRICPLSL,RSHPCPLGL,RS PLRSQANALHLRSCPCSLPLGNHPYLPC QANALHL,RSCPCSLPL,SPMSPHLRY,SLPLGNHPY,ESPMSP LESQPCLSLGNHLCPLCPRSCRCPHLGS HLR,PMSPHLRYR,NLPCPHRLR,SLPRPLHLR,LLPHHRRTR,S HPCRLS* HAYALCLR,DHICPLSLR,MSPHLRYRA,SPHLRYRAY,LPRPL HLRL,RPLHLRLHA,SPHHLRTPP,HPHHLRTHL,LPHHRRTRS, APGPRGRTC,CPLGLKSPL,LPLGNHPYL,CPRSCRCPH,CPHL GSHPC,YLRSRNSAP,NLRNHTCPP,WRSHPCCHY,RDHICPL SL,LESQPCLSL,EESPMSPHL,PPSLRSHAY,CPPRLRDHI,CPP GLRNRI,ESPMSPHLRY,CSLPLGNHPY,SLPLGNHPYL,SLPRP LHLRL,GLKSPLRSQA,YLPCLESQPC,RLRNLPCPHR,RLRSLP RPLH,RLHASPHHLR,GLRSHTYLRR,RSHAYALCLR,CLRSHT CPPR,SLRNCTCPPR,RSRTCLLCLR,RSHPCPLGLK,RSLPRPL HLR,RTHLLPHHRR,RSHPCCHYLR,RTCHPGLRSR,RSHTCPP SLR,RSHTCPPRLR,CTCPPRLRSR,RSHACPPNLR,RSHACPP GLR,RSAQNALHLR,RYRAYPPCLW,LWCHACLHRL,HLRYR AYPPC,RNLPCPHRLR,HLRLHASPHH,HLRTPPHPHH,RTPP HPHHLR,HLRTHLLPHH,HLLPHHRRTR,RTRSCPCRWR,RSC PCRWRSH,RWRSHPCCHY,RSRNSAPGPR,RGRTCHPGLR, GLRSRTCPPG,RSRTCPPGLR,RSHTYLRRLR,HTYLRRLRSH,R LRSHTCPPS,SLRSHAYALC,RLRDHICPLS,RLRSRTCLLC,RN HTCPPSLR,SLRSHACPPG,GLRNRICPLS,RNRICPLSLR,SLRS HPCPLG,KSPLRSQANA,MSPHLRYRAY,SPMSPHLRYR,CL WCHACLHR,CPHRLRSLPR,HPCCHYLRSR,HACPPGLRNR,L PCPHRLRSL,RPLHLRLHAS,SPHHLRTPPH,HPHHLRTHLL,L PHHRRTRSC,PPRLRSRTCL,SPLRSQANAL,CPRSCRCPHL,Y LRSRNSAPG,YLRRLRSHTC,HAYALCLRSH,LRYRAYPPCL,R AYPPCLWCH,HRLRSLPRPL,LRSLPRPLHL,LHLRLHASPH,LR LHASPHHL,LRTPPHPHHL,HHLRTHLLPH,WRSHPCCHYL,C HYLRSRNSA,LRSHTYLRRL,LRSHTCPPSL,LRSHAYALCL,LRS HTCPPRL,LRNCTCPPRL,LRSHACPPNL,LRNHTCPPSL,LRSH ACPPGL,LRNRICPLSL,LSLRSHPCPL,LRSQANALHL,SQANA LHLRS,LHLRSCPCSL,LRSCPCSLPL,LSLGNHLCPL,CPPGLRS HTY,CPPSLRSHAY MLL2 c.1966de|C p.L656f EDSPMSPPPEESPMSPPPEVSRLSP[p.L RLHASPHHL,SLRSHAYAL,RLRDHICPL,SLGNHLCPL,RLRSR STAD s 656fs]CLWCHACLHRLRNLPCPHRLRSL TCLL,GLRNRICPL,SLRSHPCPL,HLRSCPC5L,HLGSHPCRL,H PRPLHLRLHASPHHLRTPPHPHHLRTHL LRTHLLPH,GLRSHTYLR,RTHLLPHHR,SQANALHLR,RLRNL LPHHRRTRSCPCRWRSHPCCHYLRSRN PCPH,RLRSLPRPL,RSLPRPLHL,HLRLHASPH,HLRTPPHPH, SAPGPRGRTCHPGLRSRTCPPGLRSHTY RTPPHPHHL,RTRSCPCRW,RWRSHPCCH,RSHPCCHYL,HY LRRLRSHTCPPSLRSHAYALCLRSHTCPP LRSRNSA,RSRNSAPGP,RGRTCHPGL,RSRTCPPGL,RSHTYL RLRDHICPLSLRNCTCPPRLRSRTCLLCL RRL,HTYLRRLRS,RLRSHTCPP,RSHTCPPSL,RSHAYALCL,RS RSHACPPNLRNHTCPPSLRSHACPPGLR HTCPPRL,RSRTCLLCL,RSHACPPNL,RNHTCPPSL,RSHACP NRICPLSLRSHPCPLGLKSPLRSQANALH PGL,RNRICPLSL,RSHPCPLGL,RSQANALHL,RSCPCSLPL,SL LRSCPCSLPLGNHPYLPCLESQPCLSLGN PLGNHPY,NLPCPHRLR,SLPRPLHLR,LLPHHRRTR,SHAYAL HLCPLCPRSCRCPHLGSHPCRLS* CLR,DHICPLSLR,EVSRI,PCL,LPRPLHLRL,RPLHLRLHA,SPH HLRTPP,HPHHLRTHL,LPHHRRTRS,APGPRGRTC,CPLGLKS PL,LPLGNHPYL,CPRSCRCPH,CPHLGSHPC,YLRSRNSAP,NL RNHTCPP,VSRLSPCLW,WRSHPCCHY,RDHICPLSL,LESQP CLSL,PPSLRSHAY,CPPRLRDHI,CPPGLRNRI,CSLPLGNHPY, RLSPCLWCHA,SLPLGNHPYL,SLPRPLHLRL,GLKSPLRSQA,Y LPCLESQPC,RLRNLPCPHR,RLRSLPRPLH,RLHASPHHLR,GL RSHTYLRR,RSHAYALCLR,CLRSHTCPPR,SLRNCTCPPR,RSR TCLLCLR,RSHPCPLGLK,RSLPRPLHLR,RTHLLPHHRR,RSHP CCHYLR,RTCHPGLRSR,RSHTCPPSLR,RSHTCPPRLR,CTCP PRLRSR,RSHACPPNLR,RSHACPPGLR,RSQANALHLR,LWC HACLHRL,RNLPCPHRLR,HLRLHASPHH,HLRTPPHPHH,RT PPHPHHLR,HLRTHLLPHH,HLLPHHRRTR,RTRSCPCRWR,R SCPCRWRSH,RWRSHPCCHY,RSRNSAPGPR,RGRTCHPGL R,GLRSRTCPPG,RSRTCPPGLR,RSHTYLRRLR,HTYLRRLRSH, RLRSHTCPPS,SLRSHAYALC,RLRDHICPLS,RLRSRTCLLC,R NHTCPPSLR,SLRSHACPPG,GLRNRICPLS,RNRICPLSLR,SL RSHPCPLG,KSPLRSQANA,CLWCHACLHR,CPHRLRSLPR,H PCCHYLRSR,HACPPGLRNR,LPCPHRLRSL,RPLHLRLHAS,S PHHLRTPPH,HPHHLRTHLL,LPHHRRTRSC,PPRLRSRTCL,S PLRSQANAL,CPRSCRCPHL,YLRSRNSAPG,YLRRLRSHTC,H AYALCLRSH,HRLRSLPRPL,LRSLPRPLHL,LHLRLHASPH,LRL HASPHHL,LRTPPHPHHL,HHLRTHLLPH,WRSHPCCHYL,CH YLRSRNSA,LRSHTYLRRL,LRSHTCPPSL,LRSHAYALCL,LRSH TCPPRL,LRNCTCPPRL,LRSHACPPNL,LRNHTCPPSL,LRSHA CPPGL,LRNRICPLSL,LSLRSHPCPL,LRSQANALHL,SQANAL HLRS,LHLRSCPCSL,LRSCPCSLPL,LSLGNHLCPL,CPPGLRSH TY,CPPSLRSHAY MLL2 c.7061de|C p.P235 APLTPRASQVEPQSPGLGLRPQEPP[p.P RLWHLLLQV,ALAPTLTHM,LQVTQTSFA,VTQTSFALA,QVT STAD 4fs 2354fs]LPRLWHLLLQVTQTSFALAPTL QTSFAL,QTSFALAPT,LPRLWHLLL,LLQVTQTSF,GLRPQEP THMLSPH* PL,TQTSFALAP,TSFALAPTL,FALAPTLTH,RLWHLLLQVT, LAPTLTHML,LLQVTQTSFA,LQVTQTSFAL,LLLQVTQTSF,Q VTQTSFALA,QTSFALAPTL,RPQEPPLPRL,FALAPTLTHM, TQTSFALAPT MLL3 c.1066C>A p.Q356 IDQAPERSKEDANCAVCDSPGDLLD[p. LLDKFFCTT,SPGDLLDKF,SPGDLLDKFF LUAD K Q356K]KFFCTTCGQHYHGMCLDIAVT PLKRA MLL3 c.1179C>A p.N393 GMCLDIAVTPLKRAGWQCPECKVCQ[p. KCKQSGEDSK LUAD K N393K]KCKQSGEDSKMLVCDTCDKGY HTFCL MLL3 c.13488de| p.F449 TSGCHRFRCTNIYHFTCAIKAQCMF[p.F FLRTKLCFA,AIKAQCMFL,AQACMFLRTK,MFLRTKLCF,RTKL STAD T 6fs 4496fs]LRTKLCFAPCTNQREFMSKN* CFAPC,CFAPCTNQR,AIKAQCMFLR,KAQCMFLRTK,CTNQ REFMSK,CMFLRTKLCF,RTKLCFAPCT,FLRTKLCFAP,AQCM FLRTKL,FAPCTNQREF MLL5 c.197A>G p.Y66C YPHQLYTSSSHHSHSYIGLPYADHN[p.Y LPYADHNCGA TGCT 66C]CGARPPPTPPASPPPSVLISKNEVG I MLXIP c.2368A>C p.S790 NWKFWVFSILIRPLFESFNGMVSTA[p.S STARVHTLR,RVHTLRQTS,GMVSTARVH,VSTARVHTL,MV KIRC L R 790R]RVHTLRQTSLAWLDQYCSLPALR STARVHTL,VSTARVHTLR,RVHTLRQTSL,SFNGMVSTAR PTV MMA c.976C>T p.R326 RIQAEYVSALKLLRKRSQVWKPKVI[p.R CISARSGEGI CRC A C 326C]CISARSGEGISEMWDKMKDFQD LMLA MMP c.190de|A p.I64fs ENYYDLKKDVKQFVRRKDSGPVVKK[p.I KSEKCRSSL,KCRSSLDWR,KKSEKCRSSL,SEKCRSSLDW STAD 3 64fs]SEKCRSSLDWR* MMR c.2751C>A p.F917 QALQLQVLNSRFKALEAKSIHLSIN[p.F9 HLSINLFSL,NLFSLNKTL,SINLFSLNK,SIHLSINLF,KSIHLSINL, UCEC N1 L 17L]LFSLNKTLHEVLTMCHNASTSVSEL LSINLFSLNK,KSIFHLSINLF,AKSIHLSINL,IHLSINLFSL N MMR c.3037G>T p.A101 RSLPGSLANVVKSQKQVKSLPKKIN[p.A SLPKKINSL,SLKKPTVNL,KSLPKKINS,LPKKINSLK,SLPKKINS LUAD N1 3S 1013S]SLKKPTVNLTTVLIGRTQRNTDN LK,KSLPKKINSL,KINSLKKPTV IIY MMS1 c.3013G>A p.D100 ALTRLPTPVLLPYKPQVIRALAKPL[p.D1 ALAKPLNDK,LAKPLNDKK,RALAKPLNDK,ALAKPLNDKK TGCT 9 5N 005N]NDKKRLVRKEAVSARGEWFLLG SPGS MN1 c.1415C>T p.S472 APPYMNVAKRPRFDFPGSAGVDRCA[p. RCALWNGSM BLCA L S472L]LWNGSMHNGALDNHLSPSAY PGLPGE MOC c.2545T>C p.S849 NQHVFQKLSESRETKVNFGMYLMHA[p. GMYLMHAPL,YLMHAPLDL,FGMYLMHAPL,YLMHAPLDL KIRC OS P S849P]PLDLSSPCFLSVGSQVLPVLKE S,MYLMHAPLDL,APLDLSSPCF,LMHAPLDLSS NVEG MOCS c.65de|C p.P22fs MSSLEISSSCFSLETKLPLSP[p.P22fs]H* LETKLPLSPH STAD 2 MOG c.197_198i p.Q66f TRFWLLTVLYAAWWYLDRDKPRQGG[p.Q HQVLDYMEV,GLFPHLAGQ,DYMEVHEGL,KPRQGGPAH, LUAD AT2 nsG s 66fs]PAHPGHQVLDYMEVHEGLFP GPAHPGHQV,RQGGPAHPG,YMEVHEGLF,HPGHQVLDY, HLAGQDC* EVHEGLFPH,HEGLFPHLA,DYMEVHEGLF,EVHEGLFPHL, GPAHPGHQVL,RQGGPAHPGH,AHPGHQVLDY,HQVLDYM EVH,LDYMEVHEGL,MEVHEGLFPH,HPGHQVLDYM MORC c.337G>T p.D113 KRLSTLKFIGQYGNGLKSGSMRIGK[p.D SMRIGKYFI,RIGKYFILF,KYFILFTKK,SGSMRIGKY,MRIGKYF CRC 1 Y 113Y]YFILFTKKEETMTCVFFSQTFCEEE IL,GSMRIGKYF,IGKYFILFTK,MRIGKYFILF,GSMRIGKYFI,S S MRIGKYFIL,KSGSMRIGKY,SGSMRIGKYF MORC c.2219G>A p.R740 SDSAGEEDSADLKRAQKDKGLHVEV[p. VEVHVNREW,HVNREWYTGR,VEVHVNREWY CRC 2 H R740H]HVNREWYTGRVTAVEVGKHV VRWKVK MPDZ c.2410C>A p.L804I VRIGVAKPLPLSPEEGYVSAKEDSF[p.L8 SAKEDSFIY,KEDSFIYPP,VSAKEDSFIY,YVSAKEDSFI CRC 04I]IYPPHSCEEAGLADKPLFRADLALV G MPDZ c.4745de|A p.K158 KLTIHAENPDSQAVPSAAGAASGEK[p. GEKRTAPSL STAD 2fs K1582fs]RTAPSL* MPRI c.1052de|C p.A351 SSDTRQGRSEKRAFPRKRDFTNEAP[p. FTNEAPQLL,QLLSQTPRL,SQTPRLPPC,RDFTNEAPQL,SQT STAD P fs A351fs]QLLSQTPRLPPCLHTEEPSHWT PRLPPCL,CLHTEEPSHW,NEAPQLLSQT GGPRSPP* MR1 c.137C>T p.S46L DSRTHSLRYFRLGVSDPIHGVPEFI[p.S4 VPEFILVGY,GVPEFILVGY,VPEFILVGYV CRC 6L]LVGYVDSHPITTYDSVTRQKEPRAP W MRPL c.700C>A p.L234I LRLEREKRARIKARKENLERKKAKI[p.L2 ILKKFPHLA,RKKAKIILK,IILKKFPHL,KAKIILKKF,RKKAKIILKK, CRC 47 34I]ILKKFPHLAEAQKSSLV* KIILKKFPHL,LERKKAKIIL,KKAKIILKKF MRPS c.355_357d p.E119 SNKEIMEHIRKILGKNEETLREEEE[p.E1 REEEEKKQL TGCT 25 e|GAG de| 19de|]KKQLSHPANFGPRKYCLRECICE VEGQV MS4A c.295G>A p.V99 ALMSLSMGITMMCMASNTYGSNPIS[p. ISMYIGYTI,TYGSNPISM,SMYIGYTIW,MYIGYTIWG,YGSN BRCA 4A M V99M]MYIGYTIWGSVMFIISGSLSIA PISMY,NPISMYIGY,ISMYIGYTIW,MYIGYTIWGS,TYGSNPI AGIR SMY,NTYGSNPISM MS4A c.8C>T p.S3L MN[p.S3L]LMTSAVPVANSVLVVAPHN NLMTSAVPV,LMTSAVPVA,NLMTSAVPVA,MNLMTSAVP CRC,UCEC 8B GYPVTPG V MSH4 c.1392G>T p.K464 KNCNTPLLRAYYGSLEDKRFGIILE[p.K4 IILENIKTV,RFGIILENI,GIILENIKTV,RFGIILENIK,KRFGIILENI CRC N 64N]NIKTVINDDARYMKGCLNMRTQK CYA MSH4 c.2188G>A p.E730 YVPAEYSSFRIAKQIFTRISTDDDI[p.E73 KTNSSTFMK,KTNSSTFM UCEC K 0K]KTNSSTFMKEMKEIAYILHNANDKS L MSH6 c.1727A>C p.D576 GHTRAYGVCFVDTSLGKFFIGQFSD[p.D FSDARHCSR,DARHCSRFR,GQFSDARHC,SDARHCSRF,FSD TGCT A 576A]ARHCSRFRTLVAHYPPVQVLFEK ARHCSRF,KFFIGQFSDA,FFIGQFSDAR,QFSDARHCSR,GQF GNL SDARHCS,ARHCSRFRTL MSH6 c.3254_325 p.T108 LANYSRGGDGPMCRPVILLPEDTPP[p. LLPEDTPPL,LPEDTPPLL,ILLPEDTPPL,LLPEDTPPLL CRC,STAD 5insC 5fs T1085fs]LLRA* MSH6 c.3284G>A p.R109 GDGPMCRPVILLPEDTPPFLELKGS[p.R GSHHPCITK,KGSHHPCITK,ELKGSHHPCI,SHHPCITKTF,LEL CRC 5H 1095H]HHPCITKTFFGDDFIPNDILIGCE KGSHHPC EE MSLN c.202A>C p.T68P MTSARRRTDVGPRVAFTYPCTQLSP[p. QLSPPRAHR,SPPRAHRHL,TQLSPPRAH,PPRAHRHLPV PRAD L T68P]PRAHRHLPVHTVTYPCTQLSPTR AHS MST1 c.1304de|A p.N435 AETPHKPQFTFTSEPHAQLEENFCR[p.N GWIGWISGV,WISGVPSCA,RTQMGIAMG,QTRCSLRSV,R KIRP fs 435fs]TQMGIAMGPGATRWTQGPHS CSLRSVAR,AIRATHPGQ,HQSWTPQTR,HPGQSACGI,EEN TTVPCDAALMTSRHQSWTPQTRCSLRS FCRTQM,CRTQMGIAM,SLRSVARGW,ISGVPSCAW,RATH VARGWIGWISGVPSCAWLGAIRATHP PGQSA,SLRSVARGWI,SVARGWIGWI,QTRCSLRSVA,RGW GQSACGIGRASISAGGL* IGWISGV,AIRATHPGQS,WTPQTRCSLR,VPSCAWLGAI,FC RTQMGIAM,LEENFCRTQM,CSLRSVARGW,RSVARGWIG W,WISGVPSCAW MST1 c.1390A>G p.M46 FNGLLGPVQVTALYVTRLDNVTVAH[p. VTVAHVGTM,RLDNVTVAHV KIRC R 4V M464V]VGTMDGRILQVELVRSLNYLLY VSNF MTG1 c.315de|A p.L105f LNKMDLADLTEQQKIMQHLEGEGLK[p. HLEGEGLKM,LKMSFLPTV,GEGLKMSFL,GLKMSFLPTV,LE STAD s L105fs]MSFLPTV* GEGLKMSF MTG1 c.981de|C p.H327 DFLQTFRRGLLGSVMLDLDVLRGHP[p. RLCPELVRV,RLRLCPELV,RAGGMWPPR,MWPPRPPDL,VL STAD fs H327fs]RLRLCPELVRVGRAGGMWPP RGHPRLR,RGHPRLRLC,LVRVGRAGG,HPRLRLCPE,RVGRA RPPDLGG* GGMW,GMWPPRPPDL,RLRLCPELVR,VLRGHPRLRL,LVR VGRAGGM,DLDVLRGHPR,DVLRGHPRLR,HPRLRLCPEL MTIF2 c.326de|A p.N109 STKSKKVVEVWIGMTIEELARAMEK[p. AMEKTQIMY,KTQIMYMKL,RAMEKTQIM,TQIMYMKLY, STAD fs N109fs]TQIMYMKLY* MEKTQIMYM,KTQIMYMKLY,RAMEKTQIMY,MEKTQIMY MK,ARAMEKTQIM,AMEKTQIMYM MTM c.577de|A p.K193f DEALRKVATFRHGGRFPVLSYYHKK[p.K SYYHKKMGW,VLSYYHKKM,LSYYHKKMGW KICH R9 s 193fs]MGW* MTOR c.4379T>C p.L146 YAMKHFGELEIQATWYEKLHEWEDA[p. APVAYDKKM,HEWEDAPVA,KLHEWEDAPV,HEWEDAPV KIRC 0P L1460P]PVAYDKKMDTNKDDPELML AY GRMRCLE MTOR c.4448G>T p.C148 DALVAYDKKMDTNKDDPELMLGRMR[p. LMLGRMRFL,RFLEALGEW,LGRMRFLEA,RMRFLEALG,EL KIRC 3F C1483F]FLEALGEWGQLHQQCCEK MLGRMRF,GRMRFLEAL,MLGRMRFLEA,RMRFLEALGE,E WTLVNDET LMLGRMRFL,LGRMRFLEAL,MRFLEALGEW MTOR c.6644C>A p.S221 EDLRQDERVMQLFGLVNTLLANDPT[p. LLANDPTYL,LANDPTYLR,TYLRKNLSI,TLLANDPTY,TLLAN UCEC 5Y S2215Y]YLRKNLSIQRYAVIPLSTNSGLI DPTYL,LLANDPTYLR,LANDPTYLRK,NTLLANDPTY,YLRKNL GWV SIQR MTUS c.3013C>T p.R100 YPKQRTAAARNGFPPKPDPQAREAE[p. EAEWQLVLR,REAEWQLVL,AEWQLVLRL,DPQAREAEW,A STAD 2 5W R1005W]WQLVLRLKERCEQQTRQLGV EWQLVLRLK AQGELK MUC1 c.15355C>T p.P511 LPNFSSTSDKILATSKDSKDTKEIF[p.P51 DTKEIFSSI,KEIFSSINT,KDTKEIFSSI SKCM 6 9S 19S]SSINTEETNVKANNSGHESHSPAL AD MUC1 c.18466G>A p.A615 PDISPEASSSHSNSPPLTISTHKTI[p.A61 TTQTGPSGV,ITTQTGPSGV STAD 6 6T 56T]TTQTGPSGVTSLGQLTLDTSTIATS A MUC1 c.25817G>A p.R860 ESISSSPHPVTALLTLGPVKTTDML[p.R8 MLHTSSEPET CRC 6 6H 606H]HTSSEPETSSPPNLSSTSAEILATS E MUC1 c.31355_31 p.P104 GIMEHITKIPNEAAHRGTIRPVKGP[p.P RPVKGPSDI,VKGPSDIHF KICH 6 356insC 52fs 10452fs]SDIHFACQS* MUC1 c.33014C>T p.T110 VLPEVPGMVTSLVASSRAVTSTTLP[p.T AVTSTTLPI,LPILTLSPG,RAVTSTTLPI CLL 6 05I H005I]ILTLSPGEPETTPSMATSHGAE ASST MUC1 c.33778C>G p.P112 IDSWVAHPGTEASSVVPTLTVSTGE[p.P STGEAFTNI,EAFTNISLV,LTVSTGEAF,GEAFTNISL,TLTVST KIRC 6 60A 11260A]AFTNISLVTHPAESSSTLPRTTS GEAF,GEAFTNISLV RFS MUC1 c.34782C>A p.N115 YEPETTATWLTHPAETSTTVSGTIP[p.N TTVSGTIPK,GTIPKFSHR,STTVSGTIPK,TTVSGTIPKF LUSC 6 94K 11594K]KFSHRGSDTAPSMVTSPGVDT RSGVP MUC1 c.38321G> p.R127 SGCRLTLLRSEKDGAATGVDAICTH[p.R HLDPKSPGV,AICTHHLDPK HNSC 6 A 74H 12774H]HLDPKSPGVDREQLYWELSQL TNGIK MUC1 c.13244G> p.R441 LVYGLVGAGVVLMLIILVALLMLVF[p.R44 LLMLVFHSK,VFHSKREVK,LMLVFHSKR,MLVFHSKREV, BRCA 7 A 5H 15H]HSKREVKRQKYRLSQLYKWQEE ALLMLVFHSK,LVFHSKREVK,HSKREVKRQK,LLMLVFHSKR,VF DSGP HSKREVKR MUC1 c.229G>A p.V77 CQQLSQHVRTGSAANTATGTTSTNV[p. NVMEPRMYL,TSTNVMEPR,MEPRMYLSC,STNVMEPRMY, GBM 7 M V77M]MEPRMYLSCSTNPEMTSIESSV TTSTNVMEPR,NVMEPRMYLS,ATGTTSTNVM TSDT MUC1 c.3680_368 p.R122 PTAEVTSMPTSTPGERSTPLTSMPV[p. TSMPVSTHA,VSTHASGQF,MPVSTHASG,LTSMPVSTHA, KIRC 7 1insC 7fs R1227fs]STHASGQF* MPVSTHASGQ MUC1 c.3683de|A p.H122 TAEVTSMPTSTPGERSTPLTSMPVR[p. FQHLPLTPA,HLPLTPAHL,LTSMPVRPR,PVRPRQWPV,RPR KIRC 7 8fs H1228fs]PRQWPVLRLAPFQHLPLTPA QWPVLR,RQWPVLRLA,WPVLRLAPF,LRLAPFQHL,LAPFQ HL* HLPL,RLAPFQHLPL,VLRLAPFQHL,QWPVLRLAPF,PVRPR QWPVL,MPVRPRQWPV,RPRQWPVLRL,FQHLPLTPAH,TS MPVRPRQW,RQWPVLRLAP MUC1 c.6836C>A p.T227 STEATSSPTTAEGTSIPTSTLSEGT[p.T22 TLSEGTNPL,TLSEGTNPLT,GTNPLTSIPV,STLSEGTNPL,SEG TGCT 7 9N 79N]NPLTSIPVSHTLVANSEVSTLSTTP TNPLTSI,NPLTSIPVSH V MUC2 c.4703C>T p.T156 TTTVTPTPTPTGTQTPTTTPITTTT[p.T1 TTPITTTTM,TPITTTTMV,TTTTMVTPT,TTMVTPTPT,MVT TGCT 8M 568M]MVTPTPTPTGTQTPTSTPITTTT PTPTPT,TTTPITTTTM,TTPITTTTMV,TMVTPTPTPT,TPITT TVT TTMVT MUC2 c.4739C>A p.T158 TQTPTTTPITTTTTVTPTPTPTGTQ[p.T1 TQNPTSTPI,TQNPTSTPIT TGCT 0N 580N]NPTSTPITTTTTVTPTPTPTGTQT PT MUC2 c.4745C>G p.T158 TPTTTPITTTTTVTPTPTPTGTQTP[p.T1 TQTPRSTPI,GTQTPRSTPI,TPRSTPITTT KIRP 2R 582R]RSTPITTTTTVTPTPTPTGTQTPTTT MUC2 c.4790C>T p.T159 TPTPTGTATPTSTPITTTTTVTPTP[p.T1 TTTVTPTPI,TTTTVTPTPI,TTVTPTPIPT, TGCT 7I 597I]IPTGTQTPTTTPITTTTTVTPTPTPT MUC2 c.5111C>T p.T170 TTTTTVTPTPTPTGTQTPTSTPITT[p.T1 TTITTVTPT,TPITTITTV,STPITTITTV,TPITTITTVT, TGCT 4I 704I]ITTVTPTPTPTGTQTPTPTPISTTTT TPTSTPITTI MUC2 c.5117C>T p.T170 TTTVTPTPTPTGTQTPTSTPITTN[p.T1 TPITTTTMV,TTTTMVTPT,TTMVTPTPT,MVTPTPTPT,STPI TGCT 6M 706M]MVTPTPTPTGTQTPTPTPISTTT TTTTMV,TSTPITTTTM,TMVTPTPTPT,TPITTTTMVT TVT MUC2 c.5143G>A p.G171 PTGTQTPTSTPITTTTTVTPTPTPT[p.G1 STQTPTPTPI TGCT 5S 715S]STQTPTPTPISTTTTVTPTPTPTGT Q MUC2 c.5165C>T p.T172 TSTPITTTTTVTPTPTPTGTQTPTP[p.T1 IPISTTTTV,TQTPTPIPI,TPIPISTTT,TPIPISTTTT,IPISTTTTVT KIRP 2I 722I]IPISTTTTVTPTPTPTGTQTPTTTPI MUC5 c.2041A>G p.S681 YMGIFLVIETHGMAVSWDRKTSVFI[p.S KTSVFIGLH,FIGLHQDYK,VFIGLHQDY,RKTSVFIGL,GLHQD ACC B G 681G]GLHQDYKGRVCGLCGNFDDNAI YKGRV,VFIGLHQDYK,SVFIGLHQDY NDFA MUC5 c.2045A>G p.D682 MGIFLVIETHGMAVSWDRKTSVFIR[p.D6 FIRRHQDYK,KTSVFIRRH,VFIRRHQDY,VFIRRHQDYK,SVFI ACC,KIRP B G 82G]RHQDYKGRVCGLCGNFDDNAINDFAT RRHQDY MUC6 c.4707_470 p.P156 ITPNPTSTRTRTPVAHTNSATSSRP[p.P1 CTDGHFCLH,YLSNPITPS,YIPTFTHFL,FLHLFGDSK,CLHPLN KIRC 8insA 9fs 569fs]TTTLHHTLPTYREQSLLFHRSHD ANR,TYREQSLLF,SRSTFLHLF,KYSHSHHPY,SQNLYIPTF, GNILQDHHYLSNPITPSDHTSHSRSTFL LYIPTFTHF,SSRPTTTLH,TSHSRSTFL,HSRSTFLHL,RSTFLH HLFGDSKYSHSHHPYPCTDGHFCLHPL LFG,RVHPHSANN,TLHHTLPTY,LHLFGDSKY,LIKHSQNLY,FTHF NANRHDSSTDNAQGHRVHPHSANND LHTPC,LPTYREQSL,HPHSANNDA,ELIKHSQNL,HTSHSRST ADHQRDQPSPELIKHSQNLYIPTFTHFL F,TSSRPTTTL,HRSHDGNIL,GNILQDHHY,HHYLSNPIT,SKY HTPC* SHSHHP,AQGHRVHPH,IKHSQNLYI,HPYPCTDGH,IPTFTH FLH,TTLHHTLPTY,STDNAQGHRV,LIKHSQNLYI,TLHHTLPT YR,TSHSRSTFLH,TFLHLFGDSK,PTYREQSLLF,HSRSTFLHLF, HSQNLYIPTF,NLYIPTFTHF,LYIPTFTHFL,ATSSRPTTTL,SSR PTTTLHH,HTSHSRSTFL,RVHPHSANND,HQRDQPSPEL,FL HLFGDSKY,SKYSHSHHPY,ELIKHSQNLY,RPTTTLHHTL,LPT YREQSLL,HPYPCTDGHF,EQSLLFHRSH,FHRSHDGNIL,SHS RSTFLHL,HLFGDSKYSH,YSHSHHPYPC,KHSQNLYIPT,SQN LYIPTFT,YPCTDGHFCL,REQSLLFHRS,QDHHYLSNPI,IPTFT HFLHT MUC6 c.5930C>A p.P197 AHTTSASSSRLPTPFTTHSPPTGSS[p.P1 SHFSSTGPM,SSHFSSTGPM,HSPPTGSSHF,SHFSSTGPMT TGCT 7H 977H]HFSSTGPMTATSFQTTTTYPTPS HPQ MUC6 c.6000C>G p.H200 SSPFSSTGPMTATSFQTTTTYPTPS[p.H TPSQPQTTL,SQPQTTLPT,SQPQTTLPTH,QPQTTLPTHV TGCT 0Q 2000Q]QPQTTLPTHVPPFSTSLVTPSTH TVI MUC6 c.6387_638 p.2129_ SPITTQLPHLSSATTPVSTTNQLSS[p.21 STTNQLSSF,NQLSSFSPS,VSTTNQLSSF,NQLSSFSPSP STAD 9de|CTC 2130S 29_2130SS>S]FSPSPSAPSTVSSYVPSS S>S HSSPQTSSPS MUC7 c.1007C>T p.S336 PNSSPTTLAPDTSETSAAPTHQTTT[p.S APTHQTTTL,HQTTTLVTT,LVTTQTTTTK,APTHQTTTLV,HQ UCEC L 336L]LVTTQTTTTKQPTSAPGQNKISRF TTTLVTTQ LL MVK c.412de|C p.P138f YLSICRKQRALPSLDIVVWSELPPG[p.P1 RAWAPAPPT,APAPPTRCV,SELPPGRAW,RAWAPAPPTR, STAD s 38fs]RAWAPAPPTRCVWQQPS* VVWSELPPGR,WAPAPPTRCV,LPPGRAWAPA,APAPPTRC VW,SELPPGRAWA MXRA c.970G>T p.D324 EEDGGSQLILEKFQLPQWSISLNMT[p. WSISLNMTY,MTYEHGNMV,NMTYEHGNM,YEHGNMVN LUAD 5 Y D324Y]YEHGNMVNLVCDIKKPMDVYK L,NMTYEHGNMV,TYEHGNMVNL,QWSISLNMTY,LNMTY IHLNQ EHGNM,YEHGNMVNLV MYB c.1443de|A p.R481f ESSLDPPKVLPPARHSTIPLVILRK[p.R48 VILRKNGAR,ILRKNGARPA,LVILRKNGAR STAD s 1fs]NGARPAP* MYBP c.1937G>A p.R646 TNPVGEDVASIFLQWDVPDPPEAV[p. PEAVHITSV,VPDPPEAVHI UCEC C2 H R646H]HITSVGEDWAILVWEPPMYDG GKPVT MYD8 c.719T>C p.M24 TCVWSIASELIEKRLARRPRGGCRR[p.M TVVVVSDDY,RPRGGCRRT,RTVVVVSDDY,TVVVVSDDYL, CLL 8 0T 240T]TVVVVSDDYLQSKECDFQTKFAL RPRGGCRRTV SLS MYD8 c.752G>A p.S251 EKRLARRPRGGCRRMVVVVSDDYLQ[p. YLQNKECDF,VVSDDYLQNK,NKECDFQTKF DLBCL 8 N S251N]NKECDFQTKFALSLSPGAHQK RLIPI MYD8 c.818T>C p.L273 YLQSKECDFQTKFALSLSPGAHQKR[p.L HQKRPIPIK,RPIPIKYKA,QKRPIPIKY,AHQKRPIPIK,QKRPIPI CLL,DLB 8 P 273P]PIPIKYKAMKKEFPSILRFITVCDYT KYK,HQKRPIPIKY,SPGAHQKRPI,RPIPIKYKAM CL MYEF c.967A>G p.K323 LFDRPMHVKMDDKSVPHEEYRSHDG[p. ETPQLPRGL,RSHDGETPQL,GETPQLPRGL TGCT 2 E K323E]ETPQLPRGLGGIGMGLGPGG QPISAS MYEO c.807de|G p.L269f CSTWGLPLRVAGSWLTVVTVEALGG[p. ALGGGAWEL,SLVEDVLCA,GLARWGPLC,LVEDVLCAK,KW STAD V s L269fs]GAWELGGLARWGPLCTHPQC FICPASF,SSSSSSSLV,CAKWFICPA,DVLCAKWFI,HPQCQVL QVLLLSSSTTSSSSSSSSSSLVEDVLCAK LL,VEALGGGAW,WELGGLARW,CQVLLLSSS,SFNPQNDS WFICPASFNPQNDSMR* M,SLVEDVLCAK,SSSSSSSSLV,SFNPQNDSMR,VTVEALGG GA,EALGGGAWEL,LARWGPLCTH,CQVLLLSSST,AKWFICP ASF,ASFNPQNDSM,WELGGLARWG MYEO c.905T>A p.L302 RRTGQVGPTMHPPPVSGASPLLLHH[p. LLLHHHLLL,LLHHHLLLL,SPLLLHHHL,LHHHLLLLL,LLLHHHL TGCT V H L302H]HLLLLLIIILTC* LLL,LLHHHLLLLL,SPLLLHHHLL,LHHHLLLLLI,HHHLLLLLII MYH1 c.3271_327 p.L109 MISDLEERLKKEEKTRQELEKAKRK[p.L1 KAKRKPRRG,RPAGPDRRA,KPRRGDDRPA,RPAGPDRRAA LUAD 0 2insC 1fs 091fs]PRRGDDRPAGPDRRAAGAD* MYH1 c.2977G>A p.E993 EEEAARQKLQLEKVTAEAKIKKLED[p.E KLEDKILVM,KKLEDKILVM HNSC 1 K 993K]KILVMDDQNNKLSKERKLLEERIS DL MYH1 c.3787_378 p.K126 KENADLAGELRVLGQAKQEVEHKKK[p. VEHKKKLEA,KQEVEHKKKL STAD 1 9de|AAG 3de| K1263de|]LEAQVQELQSKCSDGERAR AELNDKVHK MYH1 c.931G>A p.D311 HIFYQIMSNKKPELIDLLLISTNPF[p.D31 LISTNPFNF,STNPFNFPF,TNPFNFPFV,NPFNFPFVS,STNPF CRC 3 N 1N]NFPFVSQGEVTVASIDDSEELLATD NFPFV,LLISTNPFNF,ISTNPFNFPF N MYH4 c.2369C>T p.T790 TKVFFKAGLLGTLEEMRDEKLAQLI[p.T KLAQLIMRT,QLIMRTQAI,IMRTQAICR,AQLIMRTQA,DEK LUAD M 790M]MRTQAICRGFLMRVEFRKMME LAQLIM,LIMRTQAICR,IMRTQAICRG,RDEKLAQLIM,AQLI RRESI MRTQAI,MRTQAICRGF MYH6 c.2540C>T p.T847 AFMGVKNWPWMKLYFKIKPLLKSAE[p. LLKSAEMEK,KPLLKSAEM,KSAEMEKEM,AEMEKEMAT,E BRCA M T847M]MEKEMATMKEEFGRIKETLEK MEKEMATM,IKPLLKSAEM,LKSAEMEKEM,AEMEKEMAT SEARR M MYH7 c.4459G>A p.A148 ESQSELESSQKEARSLSTELFKLKN[p.A1 TYEESLEHL,ELFKLKNTY,LKNTYEESL,KLKNTYEESL,NTYEES KIRP 7T 487T]TYEESLEHLETFKRENKNLQEEISD LEHL,TELFKLKNTY L MYH7 c.5065C>T p.R168 NDDLKENIAIVERRNNLLQAELEEL[p.R AELEELCAV,EELCAVVEQ,AELEELCAVV,EELCAVVEQT CRC 9C 1689C]CAVVEQTERSRKLAEQELIETSE RVQ MYH8 c.2354C>T p.A785 KFGHTKVFFKAGLLGLLEEMRDEKL[p.A KLVQIITRT,VQIITRTQA,DEKLVQIIT,VQIITRTQAV,EMRDE TGCT V 785V]VQIITRTQAVCRGFLMRVEYQK KLVQI MLQR MYH8 c.3016C>A p.H100 LTEEMAGLDETIAKLSKEKKALQET[p.H LQETNQQTL,ALQETNQQTL LUAD 6N 1006N]NQQTLDDLQAEEDKVNILTKAK TKLE MYH8 c.3143G>A p.R104 LTKAKTKLEQQVDDLEGSLEQEKKL[p.R KLQMDLERA,LEQEKKLQM,LQMDLERAK,QEKKLQMDL,K CRC 8Q 1048Q]QMDLERAKRKLEGDLKLAQES LQMDLERAK TMDME MYH8 c.3349C>T p.R111 NLISKIEDEQAVEIQLQKKIKELQA[p.R1 KIKELQACI,KKIKELQAC,KKIKELQACI,KELQACIEEL LUAD 7C 117C]CIEELGEEIEAERASRAKAEKQRS DL MYO1 c.627de|C p.P209f PRPGHRSRAPELVTKKFPVDLRLPP[p.P GVWSTLLSL,RLMGTMWRA,TMWRASPGM,VWSTLLSLV, STAD 8A s 209fs]WCPCPHLPSGSWSCNDGPLETL VQAPRTWPW,WWRLMGTMW,RARPVGVWS,GTMWRA ASPCGAQPCWIGAPRARPVGVWSTLL SPG,MWRASPGMR,QPCWIGAPR,CWIGAPRAR,LLSLVQA SLVQAPRTWPWGWCQEIDWWRLMG PR,ETLASPCGA,CPHLPSGSW,APRARPVGV,RPVGVWSTL, TMWRASPGMRLWR* SLVQAPRTW,QEIDWWRLM,WRASPGMRL,RASPGMRL W,LPPWCPCPH,SPCGAQPCW,WPWGWCQEI,GVWSTLL SLV,WIGAPRARPV,TMWRASPGMR,TLLSLVQAPR,RASPG MRLWR,TWPWGWCQEI,DWWRLMGTMW,MWRASPG MRL,RARPVGVWST,GTMWRASPGM,WWRLMGTMWR, FPVDLRLPPW,APRARPVGVW,RPVGVWSTLL,GSWSCND GPL,VGVWSTLLSL,LSLVQAPRTW,LVQAPRTWPW,CQEID WWRLM,IDWWRLMGTM,WRASPGMRLW,LETLASPCGA, LPPWCPCPHL MYO1 c.326C>T p.T109 AAYKAMKRRSKDTCIVISGESGAGK[p.T GAGKMEASK,AGKMEASKY,GKMEASKYI,KMEASKYIM,SG GBM D M 109M]MEASKYIMQYIAAITNPSQRAEV AGKMEASK,GAGKMEASKY,MEASKYIMQY,GKMEASKYI ERV M,GESGAGKMEA MYO1 c.736G>A p.E246 LQKSLSSYNYIHVGAQLKSSINDAA[p.E KSSINDAAK,SINDAAKFR,KFRVVADAM,DAAKFRVVA,SSI CRC D K 246K]KFRVVADAMKVIGFKPEEIQTVY NDAAKF,SINDAAKFRV,SSINDAAKFR,AAKFRVVADA,KFR KIL VVADAMK,KSSINDAAKF,AKFRVVADAM MYO3 c.1573A>C p.N525 AVVGAQISEYLLEKSRVIHQAIGEK[p.N5 AIGEKHFHI,IGEKHFHIF,KHFHIFYYI,HFHIFYYIY,HQAIGEK CRC A H 25H]HFHIFYYIYAGLAEKKKLAHYKLPE HF,GEKHFHIFY,EKHFHIFYY,HFHIFYYIYA,IGEKHFHIFY,GE N KHFHIFYY,KHFHIFYYIY,QAIGEKHFHI,IHQAIGEKHF,AIGEK HFHIF MYO3 c.1574A>G p.N525 AVVGAQISEYLLEKSRVIHQAIGEK[p.N5 AIGEKSFHI,KSFHIFYYI,GEKSFHIFY,SFHIFYYIY,HQAIGEKS KIRC,OV A S 25S]SFHIFYYIYAGLAEKKKLAHYKLPEN F,IGEKSFHIF,EKSFHIFYY,KSFHIFYYIY,SFHIFYYIYA,IGEKSF HIFY,GEKSFHIFYY,QAIGEKSFHI,IHQAIGEKSF,HQAIGEKSF H,AIGEKSFHIF MYO5 c.1214C>T p.A405 KLVTTSETYVKTMSLQQVINARNAL[p.A VINARNALV,LVKHIYAQL,RNALVKHIY,VKHIYAQLF,ALVKH BRCA B V 405V]VKHIYAQLFGWIVEHINKALHTSL IYAQL,QVINARNALV,VINARNALVK,RNALVKHIYA,LVKHI KQ YAQLF,ARNALVKHIY MYO5 c.2123G>T p.R708 VLETIRISAAGYPSRWAYHDFFNRY[p.R FFNRYLVLV,DFFNRYLVL,FNRYLVLVK,HDFFNRYLV,AYHD LUAD B L 708L]LVLVKKRELANTDKKAICRSVLEN FFNRYL,HDFFNRYLVL LI MYO6 c.2742_274 p.Q914 EQIQKEYDALVKSSEELLSALQKKK[p.Q KTAGRGSRK,LQKKKTAGR,GSRKAEAYS,EAYSRRNGK,YSR GBM 3insA fs 914fs]TAGRGSRKAEAYSRRNGKGKKK RNGKGK,RGSRKAEAY,KTAGRGSRKA,GSRKAEAYSR,AYSR T* RNGKGK,YSRRNGKGKK MYO6 c.3538G>A p.D118 IPARQREIEMNRQQRFFRIPFIRPA[p.D FIRPANQYK,IPFIRPANQY CRC 0N 1180N]NQYKDPQSKKKGWWYAHFDG PWIARQ MYO7 c.6119C>A p.P204 KQTSEPSYPDVILIAINRHGVLLIH[p.P20 VLLIHHKTK,LLIHHKTKDL,GVLLIHHKTK,RHGVLLIHHK,HKT LUAD B 0H 40H]HKTKDLLTTYPFTKISSWSSGSTYF KDLLTTY H MYO9 c.500G>A p.R167 QPQQKDFDDLCSLPDLNEKTLLENL[p.R LQNRFKHEK,TLLENLQNR,LLENLQNRF,KTLLENLQNR,TLL CRC A Q 167Q]QNRFKHEKIYTYVGSILIVINPFKF ENLQNRF,LQNRFKHEKI L MYO9 c.6536G>A p.R217 FLRAMGLQERKETIRGVYSVIDQLS[p.R SVIDQLSQT,QTHLNTLER,LSQTHLNTL,QLSQTHLNTL CRC A 9Q 2179Q]QTHLNTLERLIFHLVRIALQEDT NRM MYO9 c.281G>T p.R94L KESGGEEWVLDANDSPVHRVLLWPR[p. RVLLWPRLA,HRVLLWPRL LUAD B R94L]LAQDEHPQEDGYYFLLQERNAD GTIK MYOC c.1478C>T p.T493 AGSLPDTFNDASPSFGLHPSPVHVC[p.T HPSPVHVCM,MEESLMSSL,CMEESLMSSL,VHVCMEESLM HNSC D M 493M]MEESLMSSLNGGSVPSELDGLD SEKD MYOC c.678de|C p.G226 ENDRNDSASQPSHQSDAGKQGLGPP[p. GKQGLGPPA STAD D fs G226fs]APP* MYOC c.910_912d p.Q310 AYARLLQQQQLFLQLQILSQQQQQQ[p. SQQQQQQHRF PRAD D e|CAG de| Q310de|]HRFSYLGMHQAQLKEPNEQ MVRNPNSSS MYOF c.495_496i p.G165 PGMGGDGEEDEGDEDRLDNAVRGPG[p. GPGAQGASW,SACSEAHQSK,AVRGPGAQGA LUAD nsG fs G165fs]AQGASWDGVGSSACSEAH QSKEQPADAVK* MYO c.188G>A p.R63Q VYTQGSTAYSSRSSAAHRRESEAFR[p.R AFRQASASS,RESEAFRQA,SEAFRQASA,RQASASSSQ,AFR HNSC M1 63Q]QASASSSQQQASQHALSSEVSRK QASASSS,RESEAFRQAS,RQASASSSQQ,SEAFRQASAS AAS MYO c.2962G>A p.D988 DHSKLYLKNPDKEDLGTYSVSVSDT[p.D VSVSDTNG,DTNGVSSSF,NGVSSSFVL,SVSVSDTNG,DT CESC M2 N 988N]NGVSSSFVLDPEELERLMALSNEI NGVSSSFV,SDTNGVSSSF KN MYOZ c.751G>A p.E251 LSGRRSFNRTPKGWISENIPIVITT[p.E2 TTKPTDDTTV CRC 2 K 51K]KPTDDTTVPESEDL* MYT1 c.676G>A p.E226 AAEGAASEEGEKGLFIQPEDAEEVV[p.E EVVKVTTER,AEEVVKVTT CRC K 226K]KVTTERSQDLCPQSLEDAASEESS KQ MYT1 c.1052C>A p.P351 SLECLRNQCFDLARKLSETNPQERN[p.P QERNQQQNM,QQQNMNIRQH LUAD L Q 351Q]QQQNMNIRQHVRPEEDFPGRT PDRNY N4BP c.1516C>T p.R506 STKNKKRRKKRIFNLVPNFDLLGQS[p.R LLGQSCIGV,FDLLGQSCI,LLGQSCIGVK UCEC 2L2 C 506C]CIGVKEREKCDLLTKNHGLKITLG EE NAA1 c.551C>A p.T184 RRQMDLKKGGYVVLGSRENQETQGS[p. NQETQGSKL LUAD 1 K T184K]KLSDSEEACQQKNPATEESGS DSKEP NAA1 c.1542de|T p.H514 CISAYQRLGRYGDALKKCHEVERHF[p.H HEVERHFLR STAD 6 fs 514fs]LR* NAA2 c.2420C>A p.S807 DIYELDTSGLEDTMEIQERIENSFK[p.S8 YLLDQLKDV,RIENSFKYL,IENSFKYLL,KYLLDQLKDV,YLLDQ CRC 5 Y 07Y]YLLDQLKDVFSKCKGDLLEVKDGN LKDVF,SFKYLLDQLK,QERIENSFKY,NSFKYLLDQL LK NAB1 c.216G>C p.L72F EEFLEIMALVGMASKPLHVRRLQKA[p. RLQKAFRDW,HVRRLQKAF,LQKAFRDWV,RLQKAFRDWV, LUAD L72F]FRDWVTNPGLFNQPLTSLPVSSIP HVRRLQKAFR,LHVRRLQKAF,RRLQKAFRDW,LQKAFRDW IY VT NANO c.548C>T p.S183 KTQDTGHRRGGGGGAGFRGAGKSEP RGAGKSEPL,EPLPSCSPSM,FRGAGKSEPL HNSC S3 L [p.S183L]LPSCSPSMST* NAP1L c.1058C>G p.P353 MIQKYDEPILKFLSDVSLKFSKPGQ[p.P3 RVSYTFEFH,PGQRVSYTF,QRVSYTFEF,SKPGQRVSY,RVSY TGCT 3 R 53R]RVSYTFEFHFLPNPYFRNEVLVKTYI TFEFHF,SLKFSKPGQR,FSKPGQRVSY,KPGQRVSYTF,GQRV SYTFEF,LKFSKPGQRV NAP1L c.854_855C p.P285 VTVKTIKKKQKHKGRGTVRTITKQV[p.P VQNESFFNF,KQVQNESFF,TKQVQNESF,QVQNESFFNF,V SKCM 4 C>AA Q 285Q]QNESFFNFFNPLKASGDGESLDE QNESFFNFF,ITKQVQNESF,TKQVQNESFF DSEF NAPS c.362G>A p.R121 DTGSSNLWVPSRRCHFFSVPCWLHH[p. WLHHQFDPK,VPCWLHHQF,HQFDPKASS,WLHHQFDPKA, UCEC A Q R121Q]QFDPKASSSFQANGTKFAIQY CWLHHQFDPK,SVPCWLHHQF,QFDPKASSSF,HQFDPKA GTGRV SSS NARS c.719C>G p.P240 AFLTVSGQLHLEVMSGAFTQVFTFG[p. FTFGRTFRA,FTQVFTFGR,VFTFGRTFR,QVFTFGRTF,QVFT BRCA 2 R P240R]RTFRAENSQSRRHLAEFYMIEA FGRTFR,AFTQVFTFGR,TQVFTFGRTF EISF NAT1 c.1178T>C p.I393T IQYIHPADAVKLGQAELVVIDEAAA[p.I3 AAATPLPLV,AATPLPLVK,EAAATPLPL,TPLPLVKSL,IDEAAA TGCT 0 93T]TPLPLVKSLLGPYLVFMASTINGYE TPL,DEAAATPLP,VIDEAAATPL,AAATPLPLVK,EAAATPLPL G V,TPLPLVKSLL,DEAAATPLPL NBPF1 c.2428G>A p.E810 SSSHVEWEDAVHIIPENESDDEEEE[p.E KKGPVSPRNL MM K 810K]KKGPVSPRNLQESEEEEVPQESW DEG NBPF1 c.73C>T p.R25C MVVSAGPWSSEKAEMNILEINEKL[p.R KLCPQLAENK PAAD 4 25C]CPQLAENKQQFGNLKERCFVTQL AGF NBPF1 c.1347de|T p.D449 RELLDEKEPEVLQDSLDRCYSTPSD[p.D RCYSTPSDI,TPSDILNCL,STPSDILNCL,RCYSTPSDIL PAAD 6 fs 449fs]ILNCLT* NBPF3 c.1472A>T p.D491 QEEEEDQGPPCPRLSRELPEVVEPE[p.D LPEVVEPEV,ELPEVVEPEV KIRC V 491V]VLQDSLDRWYSTPFSYPELPDSC QPY NCAM c.2092G>T p.G698 GYSEPTVYEFSMPPKPNIIKDTLFN[p.G DTLFNCLGL,TLFNCLGLGA,IIKDTLFNCL,KDTLFNCLGL LUAD 2 C 698C]CLGLGAVIGLGVAALLLILVVTDV SC NCAP c.659G>T p.R220 VSLVTGCCYRLLENPTINHQKNRPT[p.R TLEAITHLL,KNRPTLEAI,LEAITHLLG,HQKNRPTLEA,RPTLE LUAD D2 L 220L]LEAITHLLGVALTRYNHMLSATVK AITHL,INHQKNRPTL,QKNRPTLEAI,LEAITHLLGV II NCAP c.2725de|C p.Q909 ASSADADHSPSSQGSSEAPASQPPP[p. QPPPRSEVL,RSEVLSCPL,EAPASQPPPR,SQPPPRSEVL STAD D3 fs Q909fs]RSEVLSCPL* NCAP c.1398de|A p.T466f HWRFRPRRKQDAPSQSENKKKSTKK[p. KMILTLMYI,MILTLMYIL,YILEKQRLL,ILKLTLKMI,TLKMILTL H s T466fs]ILKLTLKMILTLMYILEKQRLLLF* M,LTLMYILEK,MYILEKQRL,KKSTKKILK,KILKLTLKM,LKMIL STAD TLMY,LMYILEKQR,LKLTLKMIL,LTLKMILTL,LEKQRLLLF,KL TLKMILTL,KMILTLMYIL,YILEKQRLLL,ILTLMYILEK,MYILEK QRLL,ILEKQRLLLF,KKKSTKKILK,STKKILKLTL,TLKMILTLMY, TLMYILEKQR,ILKLTLKMIL,KKSTKKILKL,KKILKLTLKM,LTL KMILTLM,LKMILTLMYI,LMYILEKQRL NCOA c.3759_376 p.Q125 RSRELLSHHFRQQRVAMMMQQQQQ QTAAAAAAA,MQQQQQQTA,QQQQQQTAA,QQQQQTA PAAD 3 0de|GC 3fs Q[p.Q1253fs]TAAAAAAAAATATATAT AQ,QQQQTAAAA,QQQTAAAAA,QQTAAAAAA,MMMQQ AATAANPGLQPTS* QQQQT,MMQQQQQQTA,ATATATATAA,ATATATAATA, QTAAAAAAAA,TAATAANPGL,MQQQQQQTAA,QQQQQ QTAAA,QQQQQTAAAA,QQQQTAAAAA,QQQTAAAAAA, QQTAAAAAAA NCOA c.1685G>A p.R562 ADWVLPGKKMGNLSQLSSGEDKWLL LLQKKAQEV,LQKKAQEVL,WLLQKKAQEV,LLQKKAQEVL,L CRC 4 Q [p.R562Q]QKKAQEVLLNSPLQEEHNFP QKKAQEVLL PDHYGL NCOA c.1107G>T p.E369 DSRPIVPLEKSTGHTPTKPSGSSVS[p.E3 SSVSDKLKK,GSSVSDKLKK UCEC 7 D 69D]DKLKKLDSSRETSHGSPTVTKLSKE P NCOR c.4682G>A p.R156 PGVDPWSHSPFDPHHRGSTAGEVY[p. YQSHLPTHL,EVYQSFILPT,VYQSHLPTHL,EVYQSHLPTF,GE HNSC 1 IQ R1561Q]QSHLPTHLDPAMPFHRALDP VYQSHLPT AAAAYL NCR1 c.772C>T p.R258 TYLLTTETGLQKDHALWDHTAQNLL[p. LLWMGLAFL,WMGLAFLVL,AQNLLWMGL,LWMGLAFLV, UCEC W R258W]WMGLAFLVLVALVWFLVED HTAQNLLWM,NLLWMGLAF,NLLWMGLAFL,LLWMGLAF WLSRKRT LV,WMGLAFLVLV,AQNLLWMGLA,LWMGLAFLVL,QNLL WMGLAF NDST c.1279G>A p.V427I LNKKFALEHGIPTDMGYAVAPHHSG[p. GIYPVHVQL,AVAPHHSGI,IYPVHVQLY,VAPHHSGIY,GIYP LUAD 3 V427I]IYPVHVQLYEAWKKVWNIKITST VHVQLY,AVAPHHSGIY,YAVAPHHSGI,APHHSGIYPV,SGIY EEY PVHVQL NEDD c.570_572d p.P194 DMEHGWEVVDSNDSASQHQEELPPP[p. HQEELPPPL,LPPPLPPGW CLL 4L e|TCC de| P194de|]LPPGWEEKVDNLGRTYYVN HNNRTTQWH NEDD c.2392G>A p.A798 RNKVMNSSNQLCEQLKTIVMATKMA[p. VMATKMATL,TLHYPSTTA,ATKMATLHY,KMATLHYPS,M CRC 9 T A798T]TLHYPSTTALQEMVHQVTDL ATKMATLHY,IVMATKMATL,KMATLHYPST,TLHYPSTTAL, SRNAQL ATKMATLHYP,ATLHYPSTTA,VMATKMATLH,TKMATLHY PS NEDD c.946G>A p.A316 ARRHQSLSPNHPPPQLGQSVGSQND[p. SVGSQNDTY,DTYDVPRGV,TYDVPRGVQF,QSVGSQNDTY CRC 9 T A316T]TYDVPRGVQFLEPPAETSEKAN PQER NEFH c.1933G>A p.E645 SPVKEEAKSPAEVKSPEKAKSPTKE[p.E6 KAKSPTKEK,KSPTKEKAK,KEKAKSPEK,KAKSPTKEKA,KEKA KIRP K 45K]KAKSPEKAKSPEKEEAKSPEKAKSP KSPEKA V NEFH c.1993_199 p.665_ PTKEEAKSPEKAKSPEKEEAKSPEK[p.66 EEAKSPVKA,KEEAKSPVKA ACC,KIRP 4insAGGAA 666ins 5_666insEE]EEAKSPVKAEAKSPEKAKS G EE PVKAEAKSPEKA NEFH c.2009T>A p.V670 EAKSPEKAKSPEKEEAKSPEKAKSP[p.V6 KSPEKAEAK,KAKSPEKAEA TGCT E 70E]EKAEAKSPEKAKSPVKAEAKSPEKA K NEFM c.638C>T p.A213 RFEEEARLRDDTEAAIRALRKDIEE[p.A2 ALRKDIEEV,EVSLVKVEL,RKDIEEVSL,IEEVSLVKV,VSLVKVE STAD V 13V]VSLVKVELDKKVQSLQDEVAFLRS LDK,EEVSLVKVEL NH NEK1 c.1822C>T p.R608 EVYLARLRQIRLQNFNERQQIKAKL[p.R KAKLCGEKK,QIKAKLCGEK CRC C 608C]CGEKKEANHSEGQEGSEEADMR RKKI NEK11 C.1121G>A p.R374 KLQAADEKARKLKKIVEEKYEENSK[p.R NSKQMQELR,QMQELRSRNF,EKYEENSKQM,KQMQELRS UCEC Q 374Q]QMQELRSRNFQQLSVDVLHEKT RN HLKG NEK2 c.715C>A p.R239 PPFTAFSQKELAGKIREGKFRRIPY[p.R2 KFRRIPYSY,SYSDELNEI,IPYSYSDEL,SYSDELNEII,KFRRIPYS LUAD S 39S]SYSDELNEIITRMLNLKDYHRPSVE YS,GKFRRIPYSY,YSYSDELNEI E NEK8 c.2070de|C p.V690 VTSVSCCHGNTLLAVRSVTDEPVPP[p.V EPVPPEAPGF STAD fs 690fs]EAPGFTSGPP* NELL2 c.509G>A p.G170 QTHLNSGVILSIHHLDHRYLELESS[p.G1 ESSDHRNEV,ESSDHRNEVR,LESSDHRNEV TGCT D 70D]DHRNEVRLHYRSGSHRPHTEVFPY IL NES c.1831G>C p.V611 LKSLEKENKELLKDVEVVRPLEKEA[p.V6 LEKEALGQL,ALGQLKPTGK,KEALGQLKPT KIRC L 11L]LGQLKPTGKEDTQTLQSLQKENQE LM NF1 c.2027_202 p.T676f PGASLRKGKGNSSMDSAAGCSGTPP[p. QTRSGPVHV,RSGPVHVSV,SPDQTRSGPV STAD 8insC s T676fs]DLPTSPDqTRSGPVHVSVEP* NF1 c.4974_497 p.F165 AKPYEIVVDLTHTGPSNRFKTDFLS[p.F1 KTDFLSGLL,FLSGLLFFL,GLLFFLALL,FLALLTTTS,DFLSGLLF GBM 7de|TCTC 8fs 658fs]GLLFFLALLTTTSPQSISITVTPGS F,RFKTDFLSG,TTSPQSISI,STPSIMSGC,SPQSISITV,FKTDFL GSTPSIMSGC* SGL,TDFLSGLLF,SGLLFFLAL,GSGSTPSIM,KTDFLSGLLF,FL SGLLFFLA,LLFFLALLTT,FLALLTTTSP,LLTTTSPQSI,DFLSGLL FFL,RFKTDFLSGL,TTTSPQSISI,TSPQSISITV,TPGSGSTPSI,F KTDFLSGLL,TDFLSGLLFF,LSGLLFFLAL NFASC c.766G>A P.V256I QFEEDQFQPGVWHDHSKYPGSVNSA[p. AILRLSPYV,GSVNSAILR,SAILRLSPY,YPGSVNSAI,NSAILRL CRC V256I]ILRLSPYVNYQFRVIAINEVGSS SPY,SAILRLSPYV,KYPGSVNSAI,ILRLSPYVNY,YPGSVNSAIL HPS NFAT5 c.2716C>G p.Q906 QQQQQQQQVMESSAAMVMEMQQS EMQQSICEA,SICEAAAQI,MQQSICEAA,CEAAAQIQS,QSIC KIRC E IC[p.Q906E]EAAAAIQSELFPSTASANG EAAAQI,EAAAQIQSEL,MEMQQSICEA,MQQSICEAAA NLQQSPV NFE2L c.100C>G p.R34G PGLPSQQDMDLIDILWRQDIDLGVS[p. IDLGVSGEVF,LGVSGEVFDF BLCA 2 R34G]GEVFDFSQRRKEYELEKQKKLEK ERQ NFE2L c.101G>A p.R34Q PGLPSQQDMDLIDILWRQDIDLGVS[p. IDLGVSQEVF,LGVSQEVFDF LUSC 2 R34Q]QEVFDFSQRRKEYELEKQKKLEK ERQ NFE2L c.235G>A p.E79K LEKERQEQLQKEQEKAFFAQLQLDE[p. QLDEKTGEFL,LQLDEKTGEF,DEKTGEFLPI BLCA,HNSC 2 E79K]KTGEFLPIQPAQHIQSETSGSANY SQ NFE2L c.235G>C p.E79Q LEKERQEQLQKEQEKAFFAQLQLDE[p. AQLQLDEQT,QLDEQTGEF,EQTGEFLPI,QLDEQTGEFL,LQL HNSC,LUSC 2 E79Q]QTGEFLPIQPAQHIQSETSGSAN DEQTGEF,DEQTGEFLPI YSQ NFE2L c.241G>A p.G81S KERQEQLQKEQEKAFFAQLQLDEET[p. QLDEETSEF,EETSEFLPI,SEFLPIQPA,QLDEETSEFL,LQLDEE LUSC 2 G81S]SEFLPIQPAQHIQSETSGSANYSQ TSEF,DEETSEFLPI,SEFLPIQPAQ VA NFE2L c.85G>C p.D29H LELPPPGLPSQQDMDLIDILWRQDI[p. ILWRQDIHL,HLGVSREVF,DIHLGVSREV,IHLGVSREVF CESC,HNSC, 2 D29H]HLGVSREVFDFSQRRKEYELEKQ LUSC KKL NFE2L c.88C>T p.L30F ELPPPGLPSQQDMDLIDILWRQDID[p. ILWRQDIDF,IDFGVSREV,IDFGVSREVF,FGVSREVFDF LUSC 2 L30F]FGVSREVFDFSQRRKEYELEKQKK LE NFE2L c.92G>C p.G31A LPPPGLPSQQDMDLIDILWRQDIDL[p. DLAVSREVF,WRQDIDLAV,AVSREVFDF,ILWRQDIDLA,IDL LUSC 2 G31A]AVSREVFDFSQRRKEYELEKQKK AVSREVF,LAVSREVFDF LEK NFIA c.882G>C p.L294 SVTELVRVSQTPIAAGTGPNFSLSD[p.L LSDFESSSY,SDFESSSYY,FESSSYYSM,GPNFSLSDF,LSDFES LUAD F 294F]FESSSYYSMSPGAMRRSLPSTSST SSYY,SLSDFESSSY,FESSSYYSMS SS NHEJ1 c.326G>A p.R109 LKDAAHPSEATFSCDCVADALILRV[p.R RVQSELSGL,QSELSGLPF,QSELSGLPFY,ALILRVQSEL,VQSE UCEC Q 109Q]QSELSGLPFYWNFHCMLASPSLV LSGLPF,LRVQSELSGL SQH NHLR c.612de|T p.F204f DVTITNDCHVVVTDAGDRSIKVFDF[p.F LSLEANSPY,FLARSSLSL,SLEANSPYL,YLGVWRPPL,RSIKVF STAD C1 s 204fs]LARSSLSLEANSPYLGVWRPPLR DFL,SIKVFDFLA,LGVWRPPLR,EANSPYLGV,FDFLARSSL,A MGLW* NSPYLGVW,SIKVFDFLAR,DFLARSSLSL,PYLGVWRPPL,RSI KVFDFLA,LARSSLSLEA,VWRPPLRMGL,SLSLEANSPY,YLG VWRPPLR,LSLEANSPYL,LEANSPYLGV,LGVWRPPLRM,EA NSPYLGVW NHP2 C.250C>T p.R84C DAEPLEIILHLPLLCEDKNVPYVFV[p.R8 YVFVCSKQAL,NVPYVFVCSK,FVCSKQALGR GBM LI 4C]CSKQALGRACGVSRPVIACSVTIKEG NHS c.4681G>A p.D156 ATEILKSPILPKPPGELTAESPQST[p.D15 AESPQSTNDA TGCT 1N 61N]NDAHQGSQGAEALSPLSPCSPRV NAE NID2 c.3103de|C p.R103 EPTQRPPTICERWRENLLEHYGGTP[p.R GMTSTCPSA,ATSAGVWTK,SLHPWSGPR,GVWTKMAER, STAD 5fs 1035fs]GMTSTCPSAMTWATSSPCSAT VYPPSLHPW,RVYPPSLHP,MTSTCPSAM,SQAPPLRVY,WT ERATSAGVWTKMAERCRAPAPSQAPP KMAERCR,MTWATSSPC,TSAGVWTKM,HPWSGPRPG,PL LRVYPPSLHPWSGPRPGQM* RVYPPSL,LEHYGGTPG,EHYGGTPGM,STCPSAMTW,AMT WATSSP,TERATSAGV,CPSAMTWAT,AERCRAPAP,KMAE RCRAPA,GMTSTCPSAM,AMTWATSSPC,TSSPCSATER,RA TSAGVWTK,RVYPPSLHPW,WTKMAERCRA,RCRAPAPSQ A,MTSTCPSAMT,MTWATSSPCS,TSAGVWTKMA,APAPS QAPPL,APSQAPPLRV,LEHYGGTPGM,TERATSAGVW,ATS AGVWTKM,SQAPPLRVYP,CPSAMTWATS,AERCRAPAPS, TSTCPSAMTW NINL c.4096C>T p.R136 VRALQATEEKQRGAEKQSRLLEEKV[p. LLEEKVCAL,KVCALNKLV,CALNKLVSR,RLLEEKVCAL CRC 6C R1366C]CALNKLVSRIAPAALSV* NKD1 c.856_857i p.P286f AGIENYTSQFGPGSPSVAQKSELPP[p.P HLQSHSISL,AQKSELPPP,LQSHSISLP,AQKSELPPPH,QKSEL STAD nsC s 286fs]PHLQSHSISLP* PPPHL NKD2 c.1315_131 p.H447 GYAVPVIQRHEHHHHHEHHHHHHHH[p. EHHHHHHHHF TGCT 7de|CAC de| H447de]FHPS* NLK c.570de|T p.C190f KKMPNVFQNLVSCKRVFRELKMLCF[p. IMYSLPLYY,YSNLHTLTI,KMLCFLSMI,FLSMIMYSL,SMIMY STAD s C190fs]LSMIMYSLPLTYSNLHTLTILKKY SLPL,MIMYSLPLT,LTYSNLHTL,SLPLTYSNL,NLHTLTILK,HT MLSQN* LTILKKY,LTILKKYML,MLCFLSMIM,RELKMLCFL,LKMLCFL SM,LCFLSMIMY,SNLHTLTIL,LPLTYSNLH,MIMYSLPLTY,K MLCFLSMIM,SMIMYSLPLT,IMYSLPLTYS,FLSMIMYSLP,M LCFLSMIMY,NLHTLTILKK,SNLHTLTILK,CFLSMIMYSL,YSL PLTYSNL,TYSNLFITLTI,ELKMLCFLSM,LSMIMYSLPL,LKML CFLSMI,SNLHTLTI,LHTLTILKK,RELKMLCFLS,LPLTYSN LHT NLRC4 c.1225G>A p.E409 SDFIRSLDHCGDLALEGVFSHKFDF[p.E VFSHKFDFK,FSHKFDFKL,FKLQDVSSV,GVFSHKFDFK,VFS CRC K 409K]KLQDVSSVNEDVLLTTGLLCKYTA HKFDFKL,HKFDFKLQDV QR NLRC4 c.1777G>A p.D593 KSALSQEFEAFFQGKSLYINSGNIP[p.D5 NIPNYLFDF,INSGNIPNY,IPNYLFDFF,SGNIPNYLF,NSGNIP CRC N 93N]NYLFDFFEHLPNCASALDFIKLDFY NYLF,GNIPNYLFDF,NIPNYLFDFF,NYLFDFFEHL,YINSGNIP G NY NLRC4 c.862C>T p.R288 ALIKENHRFKNMVIVTTTTECLRHI[p.R2 ECLRHIWQF,RHIWQFGAL,WQFGALTAE,WQFGALTAEV, BRCA W 88W]WQFGALTAEVGDMTEDSAQALI CLRHIWQFGA,TECLRHIWQF,LRHIWQFGAL,RHIWQFGA REVL LT,HIWQFGALTA NLRP3 c.469C>T p.R157 MKKDYRKKYRKYVRSRFQCIEDRNA[p. RNACLGESV,CLGESVSLNK LUAD C R157C]CLGESVSLNKRYTRLRLIKEHRS QQE NLRP4 c.685G>A p.V229I LISREWPDPAAPITEIVSQPERLLF[p.V2 SQPERLLFI,FIIDSFEEL,RLLFIIDSF,QPERLLFII,SQPERLLFII,L CRC 29I]IIDSFEELQGGLNEPDSDLCGDLME FIIDSFEEL K NLRP5 c.1175G>A p.R392 LGSVLNNDTKLCKDWAEKQPPFTLI[p.R LIHSLLRKV,TLIHSLLRK,FTLIHSLLR,PFTLIHSLL,HSLLRKVLL, CRC H 392H]HSLLRKVLLPESFLIVTVRDVGTEK PPFTLIHSL,KQPPFTLIH,TLIHSLLRKV,FTLIHSLLRK,QPPFTLI L HSL,LIHSLLRKVL NLRP5 c.2209C>T p.R737 LPINQNLDLIASSFCLQHCPYLRKI[p.R7 YLRKIWVDV,IWVDVKGIF,CPYLRKIWV,YLRKIWVDVK,PYL GBM W 37W]WVDVKGIFPRDESAEACPVVPL RKIWVDV,WVDVKGIFPR,RKIWVDVKGI,KIWVDVKGIF WMRD NLRP6 c.1832A>G p.E611 CPGVAPEVTEGAKGLEDTEEPEEEE[p.E EEGGEEPNY,EEEGGEEPNY THCA G 611G]GGEEPNYPLELLYCLYETQEDAFV RQ NME9 c.223G>A p.E75K QKMRIEVGLDLLHFALAEADRLDVL[p.E KKYRGKCEPT CRC 75K]KKYRGKCEPTFLFYAGGELVAVVR GA NMU c.53C>A p.A18E MLRTESCRPRSPAGQVA[p.A18E]EASP QVAEASPLL,EASPLLLLL,GQVAEASPL,AEASPLLLL,QVAEA ACC LLLLLLLLAWCAGACRGAPILP SPLLL,EASPLLLLLL,GQVAEASPLL,AEASPLLLLL NMU c.56C>A p.A19E MLRTESCRPRSPAGQVAA[p.A19E]ESP QVAAESPLL,GQVAAESPL,VAAESPLLL,AESPLLLLL,QVAAE ACC LLLLLLLLAWCAGACRGAPILPQ SPLLL,GQVAAESPLL,VAAESPLLLL,AESPLLLLLL NNMT c.697G>A p.E233 EQKFSSLPLGREAVEAAVKEAGYTI[p.E2 YTIKWFEVI,GYTIKWFEV,KEAGYTIKW,AVKEAGYTI,GYTI UCEC K 33K]KWFEVISQSYSSTMANNEGLFSLV KWFEVI,KWFEVISQSY,KEAGYTIKWF AR NOL9 c.172T>G p.S58A PRRRLGSLRWCGRRRLRWRLLQAQA[p. WRLLQAQAA,RWRLLQAQAA ACC S58A]AGVDWREGARQVSRAAAARRP NTATP NOLC c.1283C>T p.T428 VTTKSPAVKPAAAPKQPVGGGQKLL[p. LMRKADSSS,LMRKADSSSS CRC 1 M T428M]MRKADSSSSEEESSSSEEEKTKK MVA NOM1 c.70C>G p.R24G MAASRSAGEAGPGGSQGRVVRMK[p. RMKGRGGRG,KGRGGRGPR,QGRVVRMKGR,VVRMKGR ACC R24G]GRGGRGPRRGPAGGGEKALKRL GGR,KGRGGRGPRR KLAV NOS1 c.901_903d p.Q306 LGTETPLSTHHQMQLLQQLLQQQQQ[p. LQQQQQTQV,LLQQQQQTQV,LQQQQQTQVA BLCA AP e|CAG de| Q306de|]TQVAVAQVHLLKDQLAAE AAARLEAQAR NOTC c.7541_754 p.P251 SYSSPVDNTPSHQLQVPEHPFLTPS[p.P HPFLTPSRV CLL H1 2de|CT 4fs 2514fs]RVP* NOTC c.17_18de| p.P6fs MPALR[p.P6fs]RSAVGAAGALAVLRGP ALRRSAVGA,AAGALAVLR,RSAVGAAGA,VLRGPRACI,ALA BLCA H2 CC RACIAVSRWL* VLRGPR,MPALRRSAV,SAVGAAGAL,LRRSAVGAA,GAAGA LAVL,RACIAVSRW,ALRRSAVGAA,AVGAAGALAV,ALAVLR GPRA,RSAVGAAGAL,GALAVLRGPR,VLRGPRACIA,RACIA VSRWL,MPALRRSAVG,VGAAGALAVL NOTC c.57C>G p.C19 MPALRPALLWALLALWLC[p.C19W]W LLALWLCWA,CWAAPAHAL,ALLALWLCW,WLCWAAPAH, ACC H2 W AAPAHALQCRDGYEPCVNEGMCVTY ALLALWLCWA,LLALWLCWAA,ALWLCWAAPA,WLCWAA PAHA,WALLALWLCW,LCWAAPAHAL NOTC c.6314G>T p.R210 LSPVICGPNRSFLSLKHTPMGKKSR[p.R KSRLPSAKS,TPMGKKSRL,RLPSAKSTM,MGKKSRLPSA,KS LUAD H2 5L 2105L]LPSAKSTMPTSLPNLAKEAKDAK RLPSAKST,LPSAKSTMPT,SRLPSAKSTM GSR NOTC c.6892C>T p.R229 APAEGTHPGIAPQSRPPEGKHITTP[p.R HITTPWEPL,TPWEPLPPI,WEPLPPIVT,TTPWEPLPPI,KHIT CESC H2 8W 2298W]WEPLPPIVTFQLIPKGSIAQPA TPWEPL,WEPLPPIVTF,TPWEPLPPIV GAPQ NOX3 c.1210_121 p.C404fs SLPRLAVDGPFGTALTDVFHYPVCV[p.C RSHSLRCSS,SLRCSSEIY,VFHYPVCVR,HSLRCSSEI,LRCSSEI PRAD 1de|TG 404fs]RCRGDRSHSLRCSSEIYMVQMQ* YM,SLRCSSEIYM,CVRCRGDRSH,RSHSLRCSS,HSLRCSSEI Y,DVFHYPVCVR,RCRGDRSHSL,CSSEIYMVQM NOX5 c.1401de|T p.P467fs AVCIMEVNLLPSKVTHLLIKRPPFF[p.P4 FTIDLVTTC,RPPFFTIDL,IKRPPFFTI,PPFFTIDLV,LLIKRPPFF STAD 67fs]TIDLVTTCI* T,FTIDLVTTCI,LIKRPPFFTI NOXA c.18C>G p.D6E MASLG[p.D6E]ELVRAWHLGAQAVDR SLGELVRAW,GELVRAWHL,ELVRAWHLGA,ASLGELVRAW, ACC 1 GDWARALHLFS GELVRAWHLG NOXO c.8_9insG p.G3fs MAGP[p.G3fs]PIPSFSARGSPGADQEA FSARGSPGA,LVRRQRHLR,RQRHLRAQE,HLRAQELGR,CLL KIRC 1 PNVCLLCALVRRQRHLRAQELGRIQAA CALVRR,NVCLLCALV,LPGGGGPAA,ALVRRQRHL,QRHLR QEDPQGDLPGGGGPAAEI* AQEL,MAGPPIPSF,QEAPNVCLL,AQELGRIQA,QELGRIQA A,HLRAQELGRI,SFSARGSPGA,LVRRQRHLRA,RQRHLRAQ EL,RAQELGRIQA,NVCLLCALVR,LLCALVRRQR,ALVRRQRFI LR,APNVCLLCAL,CALVRRQRHL,AQELGRIQAA NPAS c.602A>G p.Q201 DSITPLLGHLPSDVMDQNLLNFLPEtp.Q NLLNFLPER,PEREHSEVY,REHSEVYKI,LPEREHSEV,FLPERE OV 2 R 201R]REHSEVYKILSSHMLVTDSPSPEY FISEV,LPEREHSEVY,REHSEVYKIL LK NPC1 c.1351G>A p.E451 GADVPFGPPLDIQILHQVLDLQIAI[p.E4 AIKNITASY,LQIAIKNIT,QVLDLQIAIK,IAIKNITASY,LQIAIKN CRC K 51K]KNITASYDNETVTLQDICLAPLSPY ITA N NPIP c.812C>T p.A271 QPPPPTQQHSIIDNSLSLKTPSELS[p.A2 LKTPSELSV,SELSVHSPS,LSVHSPSTL,SLKTPSELSV,LKTPSE PRAD V 71V]VHSPSTLSSTLSG* LSVH,SELSVHSPST NPM1 c.859_860i p.L287f KVEAKFINYVKNCFRMTDQEAIQDL[p.L AIQDLCLAV,AVEEVSLRK,EAIQDLCLA,QEAIQDLCL,LAVEE LAML nsTCTG s 287fs]CLAVEEVSLRK* VSLRK,EAIQDLCLAV,QEAIQDLCLA NPM1 c.861_862i p.L287f KVEAKFINYVKNCFRMTDQEAIQDL[p.L AIQDLLLAV,LLAVEEVSL,AVEEVSLRK,EAIQDLLLA,QEAIQ LAML nsCTGC s 287fs]LLAVEEVSLRK* DLLL,LLLAVEEVSL,LAVEEVSLRK,EAIQDLLLAV,QEAIQDLL LA NPM1 c.863_864i p.W28 KVEAKFINYVKNCFRMTDQEAIQDL[p. AIQDLCLAV,AVEEVSLRK,EAIQDLCLA,QEAIQDLCL,LAVEE LAML nsTCTG 8fs W288fs]CLAVEEVSLRK* VSLRK,EAIQDLCLAV,QEAIQDLCLA NPR3 c.412T>C p.Y138 LFSLVDRVAAARGAKPDLILGPVCE[p.Y ILGPVCEHA,HAAAPVARL,CEHAAAPVA,GPVCEHAAA,ILG STAD H 138H]HAAAPVARLASHWDLPMLSAG PVCEHAA,HAAAPVARLA ALAAG NPSR1 c.704G>A p.R235 YMTIVAFLVYFIPLTIISIMYGIVI[p.R235 IMYGIVIQT,IVIQTIWIK,MYGIVIQTI,QTIWIKSKT,YGIVIQTI CRC Q Q]QTIWIKSKTYETVISNCSDGKLCSSY W,IMYGIVIQTI,SIMYGIVIQT,VIQTIWIKSK,GIVIQTIWIK,M YGIVIQTIW,QTIWIKSKTY NPTX1 c.787G>A p.A263 YMYAKVKKSLPEMYAFTVCMWLKSS[p. LKSSTTPGV,WLKSSTTPGV,STTPGVGTPF GBM T A263T]TTPGVGTPFSYAVPGQANELV LIEWG NPY1 c.1111G>A p.A371 DYETIAMSTMHTDVSKTSLKQASPV[p. KQASPVTFK,QASPVTFKK,LKQASPVTF,KQASPVTFKK,SLK UCEC R T A371T]TFKKINNNDDNEKI* QASPVTF NR2C c.809G>T p.S270I HPSGVKTESAVLMTSDKAESCQGDL[p. AESCQGDLI,ITLANVVTSL,GDLITLANVV,AESCQGDLIT KIRC 1 S270I]ITLANVVTSLANLGKTKDLSQNS NEM NR4A c.941G>T p.R314 RTVQKNAKYVCLANKNCPVDKRRRN[p. RNLCQYCRF,KRRRNLCQY,NLCQYCRFQK,CPVDKRRRNL,R LUAD 2 L R314L]LCQYCRFQKCLAVGMVKEVVR RNLCQYCRF TDSLK NR5A c.238G>A p.E80K SHGEQGQMPENMQVSQFKMVNYSY KMVNYSYDK,KDLEELCPV,YSYDKDLEEL CESC 2 D[p.E80K]KDLEELCPVCGDKVSGYHYG LLTCES NRAP c.979G>A p.E327 YEEHRGKGSFPAMITPAYQNAKKAH[p. YQNAKKAHK,KAHKLASDI,KLASDIKYR,HKLASDIKY,YQNA CRC K E327K]KLASDIKYRQDFNKMKGAAHY KKAHKL,KAHKLASDIK,AYQNAKKAHK,KKAHKLASDI,AHKL HSLPA ASDIKY NRAS c.181C>A p.Q61K IEDSYRKQWIDGETCLLDILDTAG[p.Q6 LDTAGKEEY,AGKEEYSAM,ILDTAGKEEY,DTAGKEEYSA CRC,LAML,MM, 1K]KEEYSAMRDQYMRTGEGFLCVFAI SKCM,THCA NN NRAS C.182A>G p.Q61R IEDSYRKQVVIDGETCLLDILDTAG[p.Q6 LDTAGREEY,AGREEYSAM,ILDTAGREEY,AGREEYSAMR,D CLL,MM,OV, 1R]REEYSAMRDQYMRTGEGFLCVFAI TAGREEYSA SKCM,TGCT, NN THCA,UCEC NRAS C.182A>T p.Q61L IEDSYRKQVVIDGETCLLDILDTAG[p.Q6 LDTAGLEEY,AGLEEYSAM,ILDTAGLEEY,LLDILDTAGL,DTA CRC,LUAD,MM, 1L]LEEYSAMRDQYMRTGEGFLCVFAIN GLEEYSA SKCM N NRAS c.183A>C p.Q61H IEDSYRKQVVIDGETCLLDILDTAG[p.Q6 LDTAGHEEY,AGHEEYSAM,ILDTAGHEEY,DTAGHEEYSA MM 1H]HEEYSAMRDQYMRTGEGFLCVFAI NN NRAS c.183A>T p.Q61H IEDSYRKQVVIDGETCLLDILDTAG[p.Q6 LDTAGHEEY,AGHEEYSAM,ILDTAGHEEY,DTAGHEEYSA LAML 1H]HEEYSAMRDQYMRTGEGFLCVFAI NN NRAS c.34G>T p.G12C MTEYKLVVVGA[p.G12C]CGVGKSALTI LVVVGACGV,VVGACGVGK,KLVVVGACGV,VVVGACGVG CRC QLIQNHFVDEYDPTIE K NRAS c.35G>A p.G12D MTEYKLVVVGA[p.G12D]DGVGKSALT LVVVGADGV,VVGADGVGK,KLVVVGADGV,VVVGADGVG CRC,LAML,MM IQLIQNHFVDEYDPTIE K NRAS c.37G>C p.G13R MTEYKLVVVGAG[p.G13R]RVGKSALTI VVGAGRVGK,RVGKSALTI,KLVVVGAGR,AGRVGKSAL,KLV CRC,MM QLIQNHFVDEYDPTIED VVGAGRV,VVVGAGRVGK,GRVGKSALTI NRAS c.38G>A p.G13D MTEYKLVVVGAG[p.G13D]DVGKSALT VVGAGDVGK,KLVVVGAGDV,VVVGAGDVGK LAML IQLIQNHFVDEYDPTIED NRG1 C.1441G>T p.V481 VSSMTVSMPSMAVSPFMEEERPLLL[p. LLLLTPPRL,LTPPRLREK,LLLTPPRLR,EEERPLLLL, LUAD L V481L]LTPPRLREKKFDHHPQQFSSFH EERPLLLLT,LLTPPRLREK,MEEERPLLLL HNPA NRG2 c.737C>T p.T246 LKKEVGKILCTDCATRPKLKKMKSQ[p.T KMKSQMGQV,SQMGQVGEK,KLKKMKSQM,MKSQMGQ CRC M 246M]MGQVGEKQSLKCEAAAGNPQP VG,KSQMGQVGEK,KLKKMKSQMG,KMKSQMGQVG,KK SYRWF MKSQMGQV NRG4 c.63_64ins p.G21fs ANRSRRALWSQSQVVLPEWGA[p.G21 VLPEWGAVV,LPEWGAVVM,VVLPEWGAVV,VLPEWGAV CLL G fs]VVM* VM,QVVLPEWGAV NRXN C.307C>T p.R103 FETPEAYISLPKWNTKRMGSISFDF[p.R CTTEPNGLI LUAD 3 C 103C]CTTEPNGLILFTHGKPQERKDARS QK NRXN c.68C>A p.P23H MLGSDDFFYVGGSPSTADLPGS[p.P23 GSHVSNNFM,STADLPGSH,STADLPGSHV,HVSNNFMGCL, LUAD 3 H]HVSNNFMGCLKEVVYKNNDIRLELSR LPGSHVSNNF NSMC c.730G>A p.D244 YFQSNAEPRCPHCNDYWPHEIPKVF[p. KVFNPEKER,HEIPKVFNP,HEIPKVFNPE UCEC E1 N D244N]NPEKERESGVLKSNKKSLRSRQ H* NSMC c.91_92ins p.Q31fs SNSGSTGFISFSGVESALSSLKNFQ[p.Q3 FQSLYQLWY,YQLWYGHSF,SLKNFQSLY,SSLKNFQSL, KIRC E2 A 1fs]SLYQLWYGHSF* NFQSLYQLW,KNFQSLYQL,SLYQLWYGFI,SSLKNFQSLY, KNFQSLYQLW,LYQLWYGHSF,NFQSLYQLWY,LSSLKNFQSL, LKNFQSLYQL NT5C3 c.7G>C p.A3P MR[p.A3P]PPSMDRAAVARVGAVASA RPPSMDRAA,PPSMDRAAV,RPPSMDRAAV TGCT SVCALVAG NT5M c.616de|C p.P206fs AEPTPSWEHVLFTACHNQHLQLQPP[p. LQLQPPAAG,NQHLQLQPPA STAD P206fs]AAGCTRGRTTGRPFWTASGP AELDCASGSSVGL* NTM c.997G>T p.G333 IMLFEVKTTALTPWKGPGAVSEVSN[p. EVSNCTSRR LUAD C G333C]CTSRRAGCVWLLPLLVLHLLLKF * NTN4 C.175G>A p.E59K CNPRMGNLALGRKLWADTTCGQNAT[p. TTCGQNATK,ATKLYCFYS,CGQNATKLY,NATKLYCFY,KLYC CRC E59K]KLYCFYSENTDLTCRQPKCDKC FYSENT,QNATKLYCFY,DTTCGANATK,GQNATKLYCF NAAY NUAK c.517G>T p.G173 RRLSERETRHFFRQIVSAVHYCHKN[p.G AVHYCHKNCV,KNCVVHRDLK,VHYCHKNCVV,HKNCVVHR LUAD 1 C 173C]CVVHRDLKLENILLDDNCNIKIAD DL FG NUB1 c.1118G>A p.R373Q RLVHIKGNCGKEKVLFLRLYLLQGI[p.R3 YLLQGIQNY,IQNYHSGNDV CRC 73Q]QNYHSGNDVEAYEYLNKARQLFK ELY NUDT c.248C>A p.S83Y ECAQRETWEEAALHLKNVHFASVVN[p. FASVVNYFI,SVVNYFIEK,HFASVVNYF,VHFASVVNY,ASVV CRC 15 S83Y]YFIEKENYHYVTILMKGEVDVTH NYFIEK,VHFASVVNYF,HFASVVNYFI,YFIEKENYHY,NVHFA DSE SVVNY,VNYFIEKENY NUDT c.39_40ins p.W13fs MSVVPPNRSQTGW[p.W13fs]APGG QLYFWYKRA,SYQLYFWYK,YQLYFWYKR,YFWYKRAPL,RSQTGWAPG, KIRC 21 G HSVRQQVHPADEAPHPGAHHQPVPSYQ SVRQQVHPA,FWYKRAPLR,AHHQPVPSY,PSYQLYFWY,HPGAHHQPV, LYFWYKRAPLREGQLCCSQISAHEGRI* QPVPSYQLY,HQPVPSYQL,DEAPHPGAH,VPSYQLYFW,YQLYFWYKRA, PSYQLYFWYK,SYQLYFWYKR,LYFWYKRAPL,GAHHQPVPSY,HQPVPSY QLY,YFWYKRAPLR,VPSYQLYFWY,RQQVHPADEA,HHQPVP SYQL,QPVPSYQLYF,REGQLCCSQI,GQLCCSQISA,SQISAHEGRI, DEAPHPGAHH NUF2 c.1019C>T p.S340 KESLNLEDQIESDESELKKLKTEEN[p.S3 NLFKRLMIV,KTEENLFKR,LFKRLMIVK,KKLKTEENL,KLKTEE CRC L 40L]LFKRLMIVKKEKLATAQFKINKKHE NLF,EENLFKRLM,TEENLFKRL,KLKTEENLFK,NLFKRLMIVK, D LFKRLMIVKK,KKLKTEENLF,TEENLFKRLM,EENLFKRLMI NUFIP c.670de|A p.R224fs TNGYMGKGADNDGSGSESGYTTPKK[p. KLGAIVPRV,GAIVPRVVK,VPRWKTLI,KKGKLGAIV,KLGAI STAD 2 R224fs]GKLGAIVPRVVKTLI* VPRVV,AIVPRVVKTL,SGYTTPKKGK,KGKLGAIVPR,LGAIVP RVVK,TPKKGKLGAI NUFIP c.86_88de| p.Q29de| KPGQPQPQHHHSHHHPHHHPQQQQ HPQQQQQPH GBM 2 AGC Q[p.Q29de|]PHHHHHYYFYNHSHNHH HHHHHQQPHQY NUP2 c.403de|C p.L135fs DAIVDLIHDIQIVSTTRELYLEDSP[p.L13 ELYLEDSPW,RELYLEDSPW STAD 10 5fs]WS* NUP8 c.905C>T p.A302 FLTYISLLHSPGNIGKLLGPLPMHP[p.A3 PVAEDNYGY,LLGPLPMHPV,PMHPVAEDNY,HPVAEDNY CRC 8 V 02V]VAEDNYGYDACAVLCLPCVPNILVI GY A NUP9 c.40G>A p.E14K MDTEGFGELLQQA[p.E14K]KQLAAET LQQAKQLAA,KQLAAETEG,KQLAAETEGI,LLQQAKQLAA,G BRCA 3 EGISELPHVERNLQEIQQA ELLQQAKQL NYAP c.1438C>T p.P480 DKAVSYTMVYSAVKVTTHSVLPAGP[p. SVLPAGPSL,LPAGPSLGA,VLPAGPSLGA,HSVLPAGPSL TGCT 1 S P480S]SLGAGEPKTEKEISVLHGMLCTS SRP NYAP c.1310C>T p.P437 SSPPPPSTLYRTQSPHGYPKSHSTS[p.P4 SLSPVSMGR,KSHSTSLSP,YPKSHSTSL,SHSTSLSPV,STSLSP LUAD 2 L 37L]LSPVSMGRSLTPLSLKRPPPYDAVH VSM,TSLSPVSMGR,KSHSTSLSPV,HSTSLSPVSM S NYAP c.590G>A p.R197 RTEASAKPRPHSDEYSKKIPPPKPK[p.R1 KQNPNTQLS,KPKQNPNTQL,KQNPNTQLST CESC 2 Q 97Q]QNPNTQLSTSFDETYIKKHGPRRT SL NYNRI c.339de|C p.G113fs AFLGAQGLFLDCLCWSTLAYLVPGP[p. LAYLVPGPL,TLAYLVPGPL STAD N G113fs]LAP* OBSC c.13546C>T p.R451 LLLRSAQPHHAGEVTFACRDAVASA[p. AVASAWLTV,VASAWLTVL,SAWLTVLGL,AVASAWLTVL,D ACC N 6W R4516W]WLTVLGLPDPPEDAEVVARS AVASAWLTV,ACRDAVASAW,ASAWLTVLGL SHTVTL OBSC c.2721_272 p.A908 VSEPKVVFAKEQLARRKLQAEAGAS[p.A90 LQAEAGAST,AEAGASTTL,LQAEAGASTT, TGCT N 2TG>CA T 8T]TTLSCEVAQAQTEVTWYKDGK QAEAGASTTL,AEAGASTTLS KLSSSS OBSC c.2989_299 p.G997fs LDVKEPKVVFAKDQVAHSEVQAEAG[p.G9 LLPPAHHRA,AEAGGQCHA,VQRWEEAEL,LQTEAGGAA, STAD N 0insG 97fs]GQCHAELRGGPGPDGGDVVQRWEEA EEAELQLES,AELRGGPGP,AELQLESAC,GLLPPAHHRA, ELQLESACRGQGLQTEAGGAA VQAEAGGQCH,QRWEEAELQL,LESACRGQGL,LQTEAGGAAG, GRQDRCRGLQLRGQGPEGLLPPAHHR RQDRCRGLQL,LQLRGQGPEG,EEAELQLESA AQDDVCKGAVSA* OBSL1 c.4924G>A p.E164 RCAARLIVREVPVTIVRGPHDLEVT[p.E VTKGDTATF,LEVTKGDTA,EVTKGDTATF CESC 2K 1642K]KGDTATFECELSQALADVTWEK DGNA ODF2L c.1221de|A p.K407fs TTLAALKDEVVSVENELSELQEVEK[p.K KLRYKSCKK,RYKSCKKQL,LLKCIKLRY,ELQEVEKNR,KPLLKC KICH 407fs]NRKPLLKCIKLRYKSCKKQLK* IKL,CIKLRYKSC,VEKNRKPLL,LLKCIKLRYK,VEKNRKPLLK,K NRKPLLKCI,CIKLRYKSCK,RYKSCKKQLK,QEVEKNRKPL,LRY KSCKKQL ODF2L c.880G>A p.E294 DQEAKLSETISASNAWKSHYEKIVI[p.E2 KKTELEVQI,YEKIVIKKT,IVIKKTELEV,KSHYEKIVIK MM K 94K]KKTELEVQIETMKKQIINLLEDLKK M ODF4 c.181C>T p.R61C TGELGQDGRLLSSTLSLSSNRSLGQ[p.R QCQNSPLPF,SLGQCQNSPL,GQCQNSPLPF,CQNSPLPFQ GBM 61C]CQNSPLPFQWRITHSFRWMAQV W LASE ODZ1 c.1097G>T p.R366 HLFGLTWQLQPVEGELYANGVSKGN[p. KGNMGTESM,MGTESMDTTY,YANGVSKGNM,SKGNMG HNSC M R366M]MGTESMDTTYSPIGGKVSDKS TESM EKKVF ODZ1 c.7666C>T p.R255 KGIKFAIKDGIVTADIIGVANEDSR[p.R2 WLAAILNNA,NEDSRWLAA,RWLAAILNNA,WLAAILNNAH, CRC 6W 556W]WLAAILNNAHYLENLHFTIEGRD NEDSRWLAAI THY ODZ2 c.1882_188 p.W62 KAACPVLCSGNGQYSKGTCQCYSGW[p. SFLRGPRLL,RVRRAHESV,SVHRSFLRG,RSFLRGPRL,CYSG KIRC 3ins6 8fs W628fs]ERCRVRRAHESVHRSFLRGPR WERCR,SGWERCRVR,ESVHRSFLR,AHESVHRSF,HESVHR LLH* SFL,WERCRVRRA,RVRRAHESVH,RAHESVHRSF,VHRSFLR GPR,RSFLRGPRLL,SGWERCRVRR,WERCRVRRAH ODZ3 c.653C>A p.P218 SAQHHPSITSLNRNSLTNRRNQSPA[p.P QPAALPAEL,NQSPAQPAA,SPAQPAALPA,RRNQSPAQPA, LUAD Q 218Q]QPAALPAELQTTPESVQLQDSW NQSPAQPAAL,AQPAALPAEL VLGS OGDH c.233de|T p.I78fs NYVEEMYCAWLENPKSVHKSWDIFF[p. RMPEPHRAL,RALPTRVPF,ATRMPEPHR,SWDIFFATR,WD GBM I78fs]ATRMPEPHRALPTRVPFP* IFFATRM,FATRMPEPH,KSWDIFFATR,ATRMPEPHRA,RAL PTRVPFP,FATRMPEPFIR,MPEPHRALPT,TRMPEPHRAL,H RALPTRVPF,EPHRALPTRV OGDH c.2844_284 p.Y948f VAITRIEQLSPFPFDLLLKEVQKYP[p.Y94 KEVQKYPQC STAD 5insC s 8fs]QC* OGDH c.1279G>A p.A427 TKAEQFYRGDAQGKKVMSILVHGDA[p. LVHGDATFA,ATFAGQGVV,TFAGQGVVY,DATFAGQGV,IL CRC L T A427T]TFAGQGVVYETFHLSDLPSYTT VHGDATF,ATFAGQGVVY,ILVHGDATFA,SILVHGDATF NGTV OGDH c.169C>T p.R57C RLLPSRLGVQAARLLAAHDVPVFGW[p. CSRSSGPPA,VPVFGWCSR,CSRSSGPPAT,DVPVFGWCSR UCEC L R57C]CSRSSGPPATFPSSKGGGGSSYM EEM OGFO c.1430_1431 p.G477 SKAEFALDLILYCGCEGWEPEYGGF[p.G FLLLTLPKV,FFLLLTLPK,LTLPKVKMK,EYGGFFFLL,YGGFFFL PAAD D1 insGTTTTT fs 477fs]FFLLLTLPKVKMKSC* LL,GFFFLLLTL,LPKVKMKSC,WEPEYGGFF,PEYGGFFFL,EPE TT YGGFFF,FFFLLLTLPK,GWEPEYGGFF,EYGGFFFLLL,WEPEY GGFFF,GGFFFLLLTL,LLLTLPKVKM,PEYGGFFFLL,EPEYGGF FFL OGFR c.1670G>C p.S557 DEPAESPSETPGPRPAGPAGDEPAE[p. ETPSETPGPR ACC T S557T]TPSETPGPRPAGPAGDEPAESP SETP OIT3 c.1522C>A p.R508 FVGKDHKEVFLHCRVLVCGVLDERS[p. VLDERSSCA,RSSCAQGCHR LUAD S R508S]SCAQGCHRRMRRGAGGEDSA GLQGQT OLFM c.396G>T p.K132 HVLSQKFEKELSKVREYVQLISVYE[p.K1 QLISVYENK,VYENKLLNL,YENKLLNLT,QLISVYENKL,SVYEN CRC 4 N 32N]NKLLNLTVRIDIMEKDTISYTELDFE KLLNL,VQLISVYENK,YENKLLNLTV OMA1 c.1334G>A p.R445 MEFVDSLHGQPKMPEWLSTHPSHGN[p. NQVEYLDRL,PSHGNQVEY,STHPSHGNQV,HPSHGNQVEY, UCEC Q R445Q]QVEYLDRLIPQALKIREMCNC NQVEYLDRLI PPLSN ONEC c.1270T>A p.L424 TLHAIFKENKRPSKELQITISQQLG[p.L4 QLGMELSTV,ITISQQLGM,MELSTVSNF,ISQQLGMEL,QQL KIRC UT1 M 24M]MELSTVSNFFMNARRRSLDKWQ GMELST,QQLGMELSTV,GMELSTVSNF,MELSTVSNFF,SQ DEGS QLGMELST OOEP c.301C>T p.R101 TSQALLTVDIVDSGNLVEITVFGRP[p.R1 ITVFGRPCV,CVQNRVKSM,EITVFGRPCV,VEITVFGRPC LUAD C 01C]CVQNRVKSMLLCLAWFHREHRAR AEK OPLA c.2699C>A p.A900 QQEGAVFLSFKLVQGGVFQEEAVTE[p. QEEAVTEDL,VTEDLRAPGK,FQEEAVTEDL,EEAVTEDLRA TGCT H D A900D]DLRAPGKVPNCSGTRNLHDNL SDLRA OPN1 c.848C>A p.P283 STQKAEKEVTRMVVVMIFAYCVCWG[p. CVCWGHYTF,VCWGHYTFF,AYCVCWGHY,GHYTFFACF,Y LUAD LW H P283H]HYTFFACFAAANPGYAFHPL CVCWGHYTF,CVCWGHYTFF,FAYCVCWGHY,WGHYTFFA MAALPA CF OPN1 c.853G>A p.A285 QKAEKEVTRMVWMVLAFCFCWGPY[p. CFCWGPYTF,FCWGPYTFF,FCWGPYTFFA,FCFCWGPYTF, HNSC MW T A285T]TFFACFAAANPGYPFHPLMA CFCWGPYTFF ALPAFF OPRD c.80G>T p.C27F EPAPSAGAELQPPLFANASDAYPSA[p.C ASDAYPSAF,AYPSAFPSA,FPSAGANAS,YPSAFPSAG,DAYP ACC 1 27F]FPSAGANASGPPGARSASSLALAIA SAFPSA,YPSAFPSAGA,NASDAYPSAF,SAFPSAGANA,FPSA I GANASG OPRM c.1058G>A p.R353 KICVFIFAFIMPVLIITVCYGLMIL[p.R35 LMILHLKSV,YGLMILHLK,CYGLMILHL,HLKSVRMLS,MILHL CRC 1 H 3H]HLKSVRMLSGSKEKDRNLRRITRMV KSVR,ILHLKSVRM,LHLKSVRML,GLMILHLKSV,ILHLKSVR L ML,HLKSVRMLSG,LMILHLKSVR,MILHLKSVRM OPRM c.1384C>T p.R462 NFKRCFREFCIPTSSNIEQQNSTRI[p.R4 STRICQNTR,NSTRICQNTR UCEC 1 C 62C]CQNTRDHPSTANTVDRTNHQLEN LEA OPTN c.70de|C p.P24fs MSHQPLSCLTEKEDSPSESTGNGPP[p. TQTWTRLPR,QTWTRLPRR,TWPTQTWTR,WPTQTWTRL, STAD P24fs]TWPTQTWTRLPRRSCCSR* PPTWPTQTW,TWPTQTWTRL,RLPRRSCCSR,PTWPTQTW TR,PTQTWTRLPR,TQTWTRLPRR,SESTGNGPPT,ESTGNG PPTW OR10 c.217T>G p.F73V IISLNQSLHVPMYLFLLNLSVVEVS[p.F7 NLSVVEVSV,SVVEVSVSA,VEVSVSAVI,VSAVITPEM,SVVE KIRC A3 3V]VSAVITPEMLVVLSTEKTMISFVGCF VSVSAV,SVSAVITPEM,VEVSVSAVIT OR10 c.278C>A p.S93Y VVEVSFSAVITPEMLVVLSTEKTMI[p.S9 LSTEKTMIY,STEKTMIYF,MIYFVGCFA,YFVGCFAQM,KTMI CRC A3 3Y]YFVGCFAQMYFILLFGGTECFLLGA YFVGC,TMIYFVGCF,TEKTMIYFV,TMIYFVGCFA,KTMIYFV M GCF,IYFVGCFAQM,VLSTEKTMIY,YFVGCFAQMY,STEKTM IYFV,LSTEKTMIYF OR10 c.597G>T p.M19 VIHHFFCHVLSLLKLACENKTSSVI[p.M1 KTSSVIIGV,SVIIGVMLV,IIGVMLVCV,TSSVIIGVM,VIIGVM LUAD H4 9I 99I]IGVMLVCVTALIGCLFLIILSYVFIV LVCV,KTSSVIIGVM,SSVIIGVMLV,CENKTSSVII OR10J c.470T>A p.L157 DRYVAICNPLRYMVIMNKRLRIQLV[p.L QLVQGACSI,RLRIQLVQG,VQGACSIGL,RLRIQLVQGA,IQL LUAD 1 Q 157Q]QGACSIGLIVAITQVTSVFRLPFC VQGACSI,VQGACSIGLI AR OR10J c.731G>A p.R244 VPMGLVFISYVLIISTILKIASVEG[p.R24 KIASVEGQK,KIASVEGQKK,ASVEGQKKAF TGCT 1 Q 4Q]QKKAFATCASHLTVVIVHYSCASIAY OR10 c.892C>A p.L298I IVYLKPEASGDDTLIAVPYTVITPF[p.L29 VITPFISPI,FISPIIFSL,ISPIIFSLR,PYTVITPFI,ITPFIS LUAD X1 8I]ISPIIFSLRNKDMKNAFRRMMGNTV PII,TPFISPIIF,TVITPFISPI,VITPFISPII,FISPIIFSLR, A ITPFISPIIF,PFISPIIFSL,VPYTVITPFI OR10 c.615G>C p.L205 DTPPVLSLACGDTGPSELRIFILSL[p.L20 RIFILSLFV,FILSLFVLL,ILSLFVLLV,LRIFILSLF,IFILSLFVL, LUAD Z1 F 5F]FVLLVSFFFITISYAYILAAILRIPS SLFVLLVSF,LFVLLVSFF,FVLLVSFFF,RIFILSLFVL,FILSLFVLLV, FVLLVSFFFI,IFILSLFVLL,LSLFVLLVSF,SLFVLLVSFF,LFVLL VSFFF,ELRIFILSLF OR11 c.461A>C p.H154 LLTVMAFDQYLAICRPLLYPNIMTG[p.H IMTGPLCAK,MTGPLCAKL,YPNIMTGPL,GPLCAKLVI,IMTG GBM H12 P 154P]PLCAKLVILCWVCGFLWFLIPIVLI PLCAKL,LLYPNIMTGP,NIMTGPLCAK,LYPNIMTGPL,MTG S PLCAKLV,GPLCAKLVIL,YPNIMTGPLC OR13 c.25C>G p.L9V MEWENHTI[p.L9V]VVEFFLKGLSGHPR TIVVEFFLK,HTIVVEFFL,MEWENHTIV,IVVEFFLKGL,HTIVV CESC C2 LELLFFVLIFIM EFFLK,MEWENHTIVV,WENHTIWEF OR13 c.773G>A p.R258 KAFSTCSSHLTVVTLYYSPVIYTYI[p.R25 VIYTYIHPA,YIHPASSYT,IHPASSYTF,TYIHPASSY,YTYIHPAS BRCA G1 H 8H]HPASSYTFERDKVVAALYTLVTPTLN S,SPVIYTYIH,YTYIHPASSY,YIHPASSYTF,HPASSYTFER OR14 c.478G>T p.G160 DRSTCVQRATVSWLYGGLIAVMHTA[p. TACTFSLSY,HTACTFSLS,AVMHTACTF,MHTACTFSL,HTAC LUAD A16 C G160C]CTFSLSYCGSNMVHQFFCDIP TFSLSY,VMHTACTFSL,GLIAVMHTAC,IAVMHTACTF QLLAI OR1M c.205G>A p.V69I LIILAISIDSHLHTPMYFFLANLSL[p.V69I] NLSLIDFCL,SLIDFCLAT,FFLANLSLI,LANLSLIDF,NLSLIDFCL PRAD 1 IDFCLATNTIPKMLVSLQTGSKAISY A,FLANLSLIDF,YFFLANLSLI,IDFCLATNTI OR2A c.240G>A p.M80I HTPMYFFLSHLAVVDIACACSTVPQ[p. ILVNLLHPA,CSTVPQILV,TVPQILVNL,VPQILVNLL,ILVNLL LUAD 25 M80I]ILVNLLHPAKPISFAGCMTQMFL HPAK,STVPQILVNL,TVPQILVNLL FLS OR2A c.313A>T p.S105 MLVNLLHPAKPISFAGCMTQMFLFL[p. QMFLFLCFA,FLFLCFAHT,FLCFAHTEC,TQMFLFLCF,LCFAH CLL 25 C S105C]CFAHTECLLLVVMSYDRYVAICH TECL,MTQMFLFLCF,TQMFLFLCFA,FLCFAHTECL,CFAHTE PLR CLLL,QMFLFLCFAH OR2A c.212C>T p.S71L GLIWLDSRLHTPMYFFLSHLAIIDI[p.S7 HLAIIDILY,AIIDILYAS,LYASNNVPK,DILYASNNV,ILYASNN SKCM 5 1L]LYASNNVPKMLTNLGLNKRKTISFVP VP,HLAIIDILYA,ILYASNNVPK,LYASNNVPKM,SHLAIIDILY, LSHLAIIDIL,IDILYASNNV OR2A c.745G>T p.G249 TVLRMPSNEGRKKALVTCSSHLIVV[p.G IVVWMFYGA,WMFYGAATF,HLIVVWMFY,SHLIVVWMF, LUAD G2 W 249W]WMFYGAATFMYVLPSSFHSPK SSHLIVVWM,CSSHLIVVW,LIVVWMFYGA,WMFYGAATF QDNII M,SSHLIVVWMF,VWMFYGAATF,SHLIWWMFY,IWWM FYGAA OR2A c.111G>C p.W37 LVSAMKTGNQSFGTDFLLVGLFQYG[p. FQYGCINSL,CINSLLFVV,QYGCINSLL,YGCINSLLF,FQYGCI LUAD K2 C W37C]CINSLLFVVIATLFTVALTGNIMLI NSLL,CINSLLFVVI,QYGCINSLLF H OR2A c.133G>A p.V45I NQSFGTDFLLVGLFQYGWINSLLFV[p.V WINSLLFVI,SLLFVIIAT,LLFVIIATL,VIIATLFTV,IIATLFTVA,L BRCA K2 45I]IIATLFTVALTGNIMLIHLIRLNTRL FVIIATLF,WINSLLFVII,SLLFVIIATL,FVIIATLFTV,VIIATLFTV A,IIATLFTVAL,GWINSLLFVI,LLFVIIATLF OR2B c.29G>T p.G10V MKSDNHSFL[p.G10V]VDSPKAFILLGV KSDNHSFLV,FLVDSPKAF,HSFLVDSPK,FLVDSPKAFI,SFLV LUSC 11 SDRPWLELPLFVVL DSPKAF,MKSDNHSFLV OR2H c.859G>A p.V287I NPYAQGRGKFFGLFYAVGTPSLNPL[p. IYTLRNKEI GBM 1 V287I]IYTLRNKEIKRALRRLLGKERDSR ES OR2H c.615G>C p.L205 PALIRLSCEDTSYNEIQVAVASVFI[p.L20 AVASVFIFV,SVFIFVVPL,FIFVVPLSL,FVVPLSLIL,VAVASVFI LUAD 2 F 5F]FVVPLSLILVSYGAITWAVLRINSAK F,IFVVPLSLI,VASVFIFVV,VAVASVFIFV,AVASVFIFVV,FIFV VPLSLI,FVVPLSLILV,VFIFVVPLSL,IFVVPLSLIL,QVAVASVFI F,ASVFIFVVPL OR2J2 c.700G>T p.G234 LIPLILILTTYGAIARAVLSMQSTT[p.G23 MQSTTWLQK,TTWLQKVFR,QSTTWLQKV,VLSMQSTTW, LUAD W 4W]WLQKVFRTCGAHLMVVSLFFIPV LSMQSTTWL,STTWLQKVF,VLSMQSTTWL,MQSTTWLQK MCM V,SMQSTTWLQK,STTWLQKVFR,AVLSMQSTTW,QSTTW LQKVF OR2L1 c.318G>T p.M10 AYNFLSGQKGISFLGCGVQSFFFLT[p.M VQSFFFLTI,QSFFFLTIA,LTIACSEGL,IACSEGLLL,FLTIACSEG LUAD 3 6I 106I]IACSEGLLLTSMAYDRYLAICHSLY L,GVQSFFFLTI,LTIACSEGLL,VQSFFFLTIA Y OR2L1 c.724A>G p.T242 CGRVLFAVYHMHSKEGRKKAFTTIS[p.T TISAHLTVV,KAFTTISAH,AHLTVVIFY,FTTISAHLT,TTISAHL LUAD 3 A 242A]AHLTVVIFYYAPFVYTYLRPRNLR TV,SAHLTVVIF,KKAFTTISA,ISAHLTVVI,FTTISAHLTV,TTIS SP AFILTVV,TISAFILTVVI,ISAFILTVVIF,RKKAFTTISA,KAFTTIS AHL,SAHLTVVIFY,AHLTVVIFYY,KKAFTTISAH OR2L3 c.199C>A p.L67I LSMILLIFLDTHLHTPMYFLLSQLS[p.L67 QLSIIDLNY,FLLSQLSII,LLSQLSIIDL,QLSIIDLNYI, LUAD I]IIDLNYISTIVPKMASDFLSGNKSIS YFLLSQLSII,SQLSIIDLNY OR2L3 c.3G>T p.M1I [p.M1I]IENYNQTSTDFILLGFFPPSRIGL IENYNQTST LUAD FL OR2L3 c.881A>G p.K294 EDKVLAVFYTTLTPMLNPIIYSLRN[p.K2 IIYSLRNREV,RNREVMGALT,REVMGALTRV TGCT R 94R]REVMGALTRVSQRICSGKM* OR2L8 c.361C>T p.R121 CGIQSFFFLALGGAEALLLASMAYD[p.R ASMAYDCYI,SMAYDCYIA,MAYDCYIAI,CYIAICFPL,SMAY LUAD C 121C]CYIAICFPLHYLIRMSKRVCVLMIT DCYIAI,AYDCYIAICF,CYIAICFPLH G OR2L8 c.513G>T p.R171 GSWIIGSINACAHTVYVLHIPYCRS[p.R1 RSSAINHFF,IPYCRSSAI,CRSSAINHF,HIPYCRSSAI,SAINHF LUAD S 71S]SAINHFFCDVPAMVTLACMDTWV FCDV,RSSAINHFFC,YCRSSAINHF,LHIPYCRSSA,CRSSAINH YEG FF OR2L8 c.603_604d p.S201f FCDVPAMVTLACMDTWVYEGTVFLS[p. FLSHHLSRV,SLHWYFMFL,FMFLWPGSL,FLWPGSLCC,SLC KIRP e|TG s S201fs]HHLSRVSLHWYFMFLWPGSL CLPHEI,LLCTFCLHL,SLFDLQHPP,CLHLSTSKI,HLSTSKIPA,L CCLPHEICRREEESLFDLQHPPHCSNFLL LHHPHPNA,SRVSLHWYF,VSLHWYFMF,WYFMFLWPG,C CTFCLHLSTSKIPAISNRGQGSGCLLHHP SNFLLCTF,NFLLCTFCL,VFLSHHLSR,RVSLHWYFM,LSRVSL HPNAQPHHL* HWY,HPPHCSNFL,HPHPNAQPH,HPNAQPHHL,YEGTVFL SH,SHHLSRVSL,HLSRVSLHW,CRREEESLF,REEESLFDL,LQ HPPHCSN,RGQGSGCLL,GQGSGCLLH,EESLFDLQH,LHWY FMFLW,HLSRVSLHWY,VSLHWYFMFL,FMFLWPGSLC,FL WPGSLCCL,FLLCTFCLHL,HLSTSKIPAI,CLLHHPHPNA,FLSH HLSRVS,TVFLSHHLSR,TFCLHLSTSK,VFLSHHLSRV,RVSLH WYFMF,SLHWYFMFLW,YFMFLWPGSL,TSKIPAISNR,HPP HCSNFLL,LSRVSLHWYF,LQHPPHCSNF,SLFDLQHPPH,YE GTVFLSHH,LSHHLSRVSL,HHLSRVSLHW,SRVSLHWYFM,I CRREEESLF,HCSNFLLCTF,LHLSTSKIPA,GQGSGCLLHH,WP GSLCCLPH OR2M c.284de|C p.A95fs DLMLICTTVPKMAFNYLSGSKSISM[p.A VSHKFSSIY,LALNVFFWL,ALNVFFWLL,NVFFWLLWL,WLL HNSC 2 95fs]VVVSHKFSSIYHCLALNVFFWLLW WLMTAI,LLWLMTAIL,LMTAILLFA,VVSHKFSSI,ISMVVVS LMTAILLFATL* HK,SMVVVSHKF,KFSSIYHCL,IYHCLALNV,CLALNVFFW,VF FWLLWLM,LWLMTAILL,WLMTAILLF,GSKSISMVV,FSSIY HCLA,MTAILLFAT,TAILLFATL,SSIYHCLAL,SKSISMVVV,HK FSSIYHC,YHCLALNVF,HCLALNVFF,SIYHCLALNV,CLALNV FFWL,LALNVFFWLL,NVFFWLLWLM,WLLWLMTAIL,LLW LMTAILL,WLMTAILLFA,LMTAILLFAT,MTAILLFATL,VVVS HKFSSI,SISMVVVSHK,VSHKFSSIYH,ISMVVVSHKF,IYHCLA LNVF,YHCLALNVFF,FWLLWLMTAI,LWLMTAILLF,GSKSIS MVVV,KFSSIYHCLA,VVSHKFSSIY,KSISMVVVSH,HKFSSIY HCL,FSSIYFHCLAL OR2M c.531C>A p.F177 GSTDGIIDAVATFSFSFCGSREIAH[p.F1 HLFCEFPSL,GSREIAHLF,EIAHLFCEF,REIAHLFCE,HLFCEFP LUAD 2 L 77L]LFCEFPSLLILSCNDTSIFEEVIFIC SLL,REIAHLFCEF,LFCEFPSLLI,GSREIAHLFC,CGSREIAHLF, AHLFCEFPSL OR2M c.967T>C p.F323 TRAFMKILGKGKSESELPHKLYVLL[p.F3 LLLAKFFFL,LLAKFFFLI,KLYVLLLAK,LYVLLLAKF,VLLLAKFFF, LUAD 2 L 23L]LAKFFFLISIFFYDVKILALIMYIA VLLLAKFFFL,LLLAKFFFLI,KLYVLLLAKF,LYVLLLAKFF,YVLLL AKFFF,LAKFFFLISI,LPHKLYVLLL OR2M c.704G>A p.R235 PVAIIIASYARVILAVIHMGSGEGR[p.R2 SGEGRHKAF,HMGSGEGRHK,GSGEGRHKAF,HKAFTTCSS CRC 3 H 35H]HKAFTTCSSHLLWGMYYGAALF H,GEGRHKAFTT MYI OR2M c.819G>T p.M27 VGMYYGAALFMYIRPTSDRSPTQDK[p. KIVSVFYTI,TQDKIVSVF,TQDKIVSVFY,KIVSVFYTIL,SPTQD HNSC 3 3I M273I]IVSVFYTILTPMLNPLIYSLRNKE KIVSV VT OR2M c.613G>T p.V205 DFPSLLILSCNDTSIFEKVLFICCI[p.V205 FICCILMIV,CILMIVFPV,ILMIVFPVA,LMIVFPVAI,LFICCILM LUAD 5 L L]LMIVFPVAIIIASYARVILAVIHMGS I,KVLFICCIL,VLFICCILM,VLFICCILMI,ILMIVFPVAI,LMIVFP VAII,KVLFICCILM,FICCILMIVF OR2T c.551G>A p.R184 VATLSFPYCGAHEIDHFFCEAPVLV[p.R HLACADTSV,EAPVLVHLA,CEAPVLVHL,HLACADTSVF,CEA GBM 12 H 184H]HLACADTSVFENAMYICCVLMLL PVLVHLA VPF OR2T c.772A>T p.M25 KKAFATCSSHVAVVGLFYGAGIFTY[p. YGAGIFTYL,GIFTYLRPK,GAGIFTYLR,TYLRPKSHR,YLRPKS LUAD 12 8L M258L]LRPKSHRSTNHDKVVSAFYTM HRS,AGIFTYLRPK,FTYLRPKSHR,FYGAGIFTYL,YGAGIFTYL FTPLL R,YLRPKSHRST OR2T c.37T>G p.F13V MGMEGLLQNSTN[p.F13V]VVLTGLIT GLLQNSTNV,LLQNSTNVV,STNVVLTGL,LQNSTNVVL,GLL LUSC 2 HPAFPGLLFAIVFSIFVV QNSTNVV,LLQNSTNVVL,NSTNVVLTGL,STNVVLTGLI,LQ NSTNVVLT OR2T c.31G>T p.D11Y MEQSNYSVYA[p.D11Y]YFILLGLFSNA QSNYSVYAY,SVYAYFILL,YAYFILLGL,SNYSVYAYF,NYSVYA LUAD 27 RFPWLLFALILLVFL YFI,YSVYAYFIL,VYAYFILLG,AYFILLGLF,YSVYAYFILL,NYSV YAYFIL,VYAYFILLGL,YAYFILLGLF,EQSNYSVYAY,QSNYSVY AYF,SNYSVYAYFI OR2T c.358C>A p.R120 CGVQIFFLPTLGGGECFLLAAMAYD[p.R AMAYDSYAA,MAYDSYAAV,AAMAYDSYA,SYAAVCHPL,L HNSC 33 S 120S]SYAAVCHPLRYPTLMSWQLCLR AAMAYDSY,FLLAAMAYDS,AMAYDSYAAV,AAMAYDSYA MTMS A,LLAAMAYDSY,SYAAVCHPLR,LAAMAYDSYA,DSYAAVC HPL,MAYDSYAAVC OR2T c.494C>A p.P165 LRMTMSCWLLGAADGLLQAWTLSF[p. FQYCGAHEI,TLSFQYCGA,AVVTLSFQY,LSFQYCGAH,SFQY LUAD 33 Q P165Q]QYCGAHEIDHFFCETPVLVRLA CGAHEI,QAVVTLSFQY,FQYCGAHEID CADT OR2T c.737G>T p.C246 SSYTLILHLIHRMNSAAGRRKALAT[p.C ALATFSSHM,KALATFSSH,ATFSSHMII,GRRKALATF,RKAL LUAD 34 F 246F]FSSHMIIVLLLFGASFYTYMLRSSY ATFSS,FSSHMIIVL,LATFSSHMI,ALATFSSHMI,ATFSSHMII H V,FSSHMIIVLL,TFSSHMIIVL,KALATFSSHM,AGRRKALATF, RKALATFSSH,LATFSSHMII OR2T c.408_409C p.V137 KMLLDQVMGVNKISAPECGMQMFFY[p.V13 GMQMFFYLT,MQMFFYLTL,CGMQMFFYL,GMQMFFYLT LIHC 4 G>TC L 7L]LTLAGSEFFLLATMAYDRYVAI L,MQMFFYLTLA,FYLTLAGSEF CHPLR OR2T c.637G>T p.V213 ACGDKTTYETVMYVCCVAMLLIPFS[p. AMLLIPFSL,MLLIPFSLV,LLIPFSLVT,LIPFSLVTA,LVTASYTRI, LUAD 6 L V213L]LVTASYTRILITVHQMTSAEGRK SLVTASYTR,PFSLVTASY,IPFSLVTAS,AMLLIPFSLV,LLIPFSL KAF VTA,SLVTASYTRI,FSLVTASYTR,IPFSLVTASY,VAMLLIPFSL OR4C c.744C>A p.F248 LKNNSLEGRCKALSTCISHIIVVVL[p.F24 IIVVVLLFV,LLFVPCIFV,HIIVVVLLF,VLLFVPCIF,LFVPCIFVY, UCEC 12 L 8L]LFVPCIFVYLRSVTTLPIDKAVAVFY HIIVVVLLFV,VLLFVPCIFV,LLFVPCIFVY,SHIIVVVLLF,VVLLF VPCIF,LFVPCIFVYL,ISHIIVVVLL OR4C c.837G>T p.M27 FVYLRSVTTLPIDKAVAVFYTMWP[p. MVVPILNPV,ILNPVVYTL,VFYTMVVPI,FYTMVVPIL,VPILN LUAD 12 9I M279I]ILNPVVYTLRNAEVKSAIRKLWR PVVY,AVFYTMVVPI,TMVVPILNPV,MVVPILNPVV,ILNPV KKV VYTLR,VFYTMVVPIL,VVPILNPVVY OR4C c.925G>T p.D309 VYTLRNAEVKSAIRKLWRKKVTSDN[p. RKKVTSDNY,WRKKVTSDNY LUAD 12 Y D309Y]Y OR4C c.188A>T p.Y63F LGNLLIIISVKTSQALKNPMFFFLF[p.Y63 PMFFFLFFL,FLSLSDTCL,FFFLFFLSL,NPMFFFLFF,FLFFLSLS CLL 16 F]FLSLSDTCLSTSITPRMIVDALLKKT DT,FLSLSDTCLS,KNPMFFFLFF,MFFFLFFLSL,NPMFFFLFFL OR4C c.403A>C p.S135 IFILILTAVDRYVDICKPLHYMTII[p.S135 YMTIIRQWV,IIRQWVCGV,HYMTIIRQW,RQWVCGVLM,T STAD 16 R R]RQWVCGVLMAVAWVGSCVHSLVQI IIRQWVCGV,RQWVCGVLMA,HYMTIIRQWV,LHYMTIIRQ FL W,IRQWVCGVLM OR4C c.484C>A p.L162 WVCGVLMAVAWVGSCVHSLVQIFLA[p. SLVQIFLAM,VQIFLAMSL,FLAMSLPFC,IFLAMSLPF,MSLPF LUAD 16 M L162M]MSLPFCGPNVINHCFCDLQP CGPNV,FLAMSLPFCG,QIFLAMSLPF,HSLVQIFLAM,VQIFL LLKQAC AMSLP OR4C c.389_390i p.H130 IADSLYEGRTISYECCMAQLFGAHF[p.H AQLFGAHFF,LFGAHFFGR,QLFGAHFFGR,MAQLFGAHFF LUAD 3 nsT fs 130fs]FGRC* OR4E c.677G>A p.R226 TNSGTISLSCFLAVVTSYMVILVSL[p.R2 MVILVSLQK,ILVSLQKFISA,YMVILVSLQK SKCM 2 Q 26Q]QKHSAEGRQKALSTCSAHFMVVA LFF OR4K c.761G>T p.C254 SSRGSSKALSTCTAHFIVVFLFFGP[p.C2 FLFFGPFIF,FIFIYMWPL,VFLFFGPFI,LFFGPFIFI,FFGPFIFIY, LUSC 2 F 54F]FIFIYMWPLSSFLTDKILSVFYTIFT VVFLFFGPF,GPFIFIYMW,VVFLFFGPFI,FLFFGPFIFI,IVVFLF FGPF,VFLFFGPFIF,FFGPFIFIYM,FGPFIFIYMW,PFIFIYMW PL,LFFGPIFIY OR4K c.529de|T p.F177f VHTLSQLSFTVNLPFCGPNWDSFF[p.F NVVDSFFVI,FLESPNLPA,PAWTLTSLK,AWTLTSLKY,SPNLP STAD 5 s 177fs]VIFLESPNLPAWTLTSLKY* AWTL,LPAWTLTSL,VVDSFFVIF,LESPNLPAW,VVDSFFVIFL, FVIFLESPNL,NLPAWTLTSL,PAWTLTSLKY,ESPNLPAWTL, NVVDSFFVIF,FLESPNLPAW,LESPNLPAWT OR4M c.122G>A p.G41E GLSQTREVQLVLFVIFLSFYLFILP[p.G41 YLFILPENI,FILPENILI,ILPENILII,YLFILPENIL,FILPEN SKCM 1 E]ENILIICTIRLDPHLTSPMYFLLANL ILII,FYLFILPENI,LFILPENILI,ENILIICTIR OR4M c.355G>T p.A119 FDGCIAQLFFLHFAGASEMFLLTVM[p. LTVMSFDLY,LLTVMSFDL,VMSFDLYTA,MSFDLYTAI,MFLL LUAD 2 S A119S]SFDLYTAICRPLFIYATIMNQRLC TVMSF,TVMSFDLYT,LLTVMSFDLY,FLLTVMSFDL,TVMSF CIL DLYTA,VMSFDLYTAI,EMFLLTVMS,MSFDLYTAIC,SEMFL LTVMS OR4M c.481G>T p.A161 MNQRLCCILVALSWRGGFIHSIIQV[p.A SIIQVSLIV,IQVSLIVRL,SLIVRLPFC,VSLIVRLPF,HSIIQVSLI,I LUAD 2 S 161S]SLIVRLPFCGPNELDSYFCDITQVV HSIIQVSL,FIHSIIQVSL,SIIQVSLIVR,HSIIQVSLIV,QVSLIVRL R PF OR4M c.803C>T p.S268 YSHITIVVLMFGPSIYIYARPFDSF[p.S26 FFLDKVVSV,FLDKVVSVF,YARPFDSFF,IYARPFDSFF,FFLDK SKCM 2 F 8F]FLDKVVSVFNTLIFPLRNPIIYTLRN VVSVF,YARPFDSFFL,RPFDSFFLDK OR4N c.122G>A p.G41E GLTQSQDIQLLVFVLVLIFYFIILP[p.G41 FIILPENFL,IILPENFLI,ILPENFLII,YFIILPENF,ENFLIIFTI, SKCM 2 E]ENFLIIFTIKSDPGLTAPLYFFLGNL LPENFLIIF,FIILPENFLI,IILPENFLII,FYFIILPENF,YFIIL PENFL,ILPENFLIIF,PENFLIIFTI OR4N c.448_449i p.L150f ICRPLHYPTVMNPRTCYAMMLALWL[p. MLALWLWGF,AMMLALWLW,LWLWGFCPL,LWGFCPLH BLCA,KIRC 2 nsT s L150fs]WGFCPLHYPGGPHPPLAFLW Y,YPGGPHPPL,GPHPPLAFL,WPKPAGQLL,LHYPGGPHP,L PKPAGQLLL* AFLWPKPA,MMLALWLWGF,MLALWLWGFC,ALWLWGF CPL,FLWPKPAGQL,YAMMLALWLW,HYPGGPHPPL,LWP KPAGQLL,WLWGFCPLHY,WPKPAGQLLL,LHYPGGPHPP, GPHPPLAFLW OR4N c.448_449i p.L150f ICRPLHCSTVMNPRACYAMMLALWL[p. MLALWLWGF,AMMLALWLW,LWLWGFCPL,LWGFCPLH CLL 4 nsT s L150fs]WGFCPLHYPGGPHPPLAFLW Y,YPGGPHPPL,GPHPPLAFL,WPKPAGQLL,LHYPGGPHP,L PKPAGQLLL* AFLWPKPA,MMLALWLWGF,MLALWLWGFC,ALWLWGF CPL,FLWPKPAGQL,YAMMLALWLW,HYPGGPHPPL,LWP KPAGQLL,WLWGFCPLHY,WPKPAGQLLL,LHYPGGPHPP, GPHPPLAFLW OR51 c.371T>G p.L124 AQEFFIHGFTVMESSVLLIMSLDRF[p.L IMSLDRFRA,LIMSLDRFR,RFRAIHNPL,MSLDRFRAI,RAIHN STAD A7 R 124R]RAIHNPLRYSSILTSNRVAKMGLIL PLRY,IMSLDRFRAI,LIMSLDRFRA,MSLDRFRAIH,RFRAIHN A PLR,FRAIHNPLRY,LLIMSLDRFR OR51 c.488C>T p.S163 RVIALGVGVFLRGFVSILPVILRLF[p.S16 RLFLFSYCK,PVILRLFLF,ILRLFLFSY,LPVILRLFL,FLFSYCKSH, SKCM B2 L 3L]LFSYCKSHVITRAFCLHQEIMRLACA FLFSYCKSHV,ILPVILRLFL,VILRLFLFSY,LPVILRLFLF OR51 c.197_213d p.A66fs GTLLLLIKEDHNLHEPMYFFLAMLA[p.A MLAGPDHNA,LLFPGLLYT,GLLYTLTFL,LLYTLTFLS,YTLTFLS KIRC B5 e|CCACAGA 66fs]GPDHNAHGAGSPLAGSQGDWK RV,FLSRVWHSA,GLLFPGLLY,LFPGLLYTL,VWHSACHGL,LY CCTGGGGC CGLLFPGLLYTLTFLSRVWHSACHGL* TLTFLSR,NAHGAGSPL,SQGDWKCGL,GDWKCGLLF,FPGL TG LYTLT,AMLAGPDHNA,GLLFPGLLYT,LLFPGLLYTL,FLSRVW HSAC,RVWHSACHGL,LLYTLTFLSR,LYTLTFLSRV,YTLTFLSR VW,LSRVWHSACH,CGLLFPGLLY,HNAHGAGSPL,FPGLLYT LTF,MLAGPDHNAH,SQGDWKCGLL,WKCGLLFPGL,SPLA GSQGDW OR51F c.200G>C p.R67P SIPFCLLYVVAVSGNSMILFVVLCE[p.R6 VLCEPSLHK,PSLHKPMYY,CEPSLFHPM,VVLCEPSLHK,LCE LUSC 2 7P]PSLHKPMYYFLSMLSATDLSLSLCTL PSLHKPM,EPSLHKPMYY OR51S c.476G>A p.R159 ICRPLHYPALLTNGVISKISLAISF[p.R159 SLAISFQCL,SFQCLGLHL,ISFQCLGLH,FQCLGLHLPL,ISLAIS LUSC 1 Q Q]QCLGLHLPLPFLLAYMPYCLPQVLTH FQCL,LAISFQCLGL,ISFQCLGLHL OR51 c.892C>A p.P298 FGKHLSPVAHVLIGNIYILFPPLMN[p.P2 ILFPPLMNT,LMNTIIYSV,LFPPLMNTI,MNTIIYSVK,NTIIYSV LUAD V1 T 98T]TIIYSVKTQQIHTRMLRLFSLKRY KT,PPLMNTIIY,FPPLMNTII,ILFPPLMNTI,PLMNTIIYSV,LM NTIIYSVK,LFPPLMNTII,FPPLMNTIIY OR52 c.397C>T p.R133 FVHALTAMESGVLLAMACDRAAAIG[p. RAAAIGCPL,AAIGCPLHY,CPLHYPVLV,AIGCPLHYPV,RAA CRC W1 C R133C]CPLHYPVLVTKACVGYAALALA AIGCPLH,AAAIGCPLHY,IGCPLHYPVL LKAV OR5A c.267G>T p.K89N QHLAFVDICYTSAITPKMLQSFTEE[p.K8 FTEENNLML,TEENNLMLF,FTEENNLMLF,LQSFTEENNL,Q UCEC K2 9N]NNLMLFQGCVIQFLVYATFATSDCY SFTEENNLM L OR5A c.117G>T p.M39I FVGFTDYLPLRVTLFLVFLLVYTLT[p.M3 FLLVYTLTI,LLVYTLTIV,YTLTIVGNI,TIVGNILLI,LTIVGNILL,F LUAD S1 9I]IVGNILLIILVNINSSLQIPMYYFLS LLVYTLTIV,VFLLVYTLTI,VYTLTIVGNI,YTLTIVGNIL,LTIVGN ILLI OR5A c.935G>A p.R312 KAFSTCASHLTAICLFFGTTLFMYL[p.R3 FMYLHPRSS,YLHPRSSYS,TLFMYLHPR,GTTLFMYLH,MYL CRC U1 H 12H]HPRSSYSLTQDRTVAVIYTVVIPVL HPRSSY,HPRSSYSLT,LHPRSSYSL,YLHPRSSYSL,FMYLHPRS N SY,TTLFMYLHPR OR5B c.865A>T p.S289 HFMGTDKMASVFYAIVIPMLNPLVY[p. MLNPLVYCL,LVYCLRNKEV,MLNPLVYCLR,CLRNKEVKSA LUAD 12 C S289C]CLRNKEVKSAFKKTVGKAKASIG FIF OR5B c.488G>A p.R163 VCACLAIGCYVIGFLNASIQIGDTF[p.R1 IQIGDTFHL,HLSFCMSNV,DTFHLSFCM,IGDTFHLSF,HLSFC CRC 17 H 63H]HLSFCMSNVIHHFFCDKPAVITLTC MSNVI,DTFHLSFCMS,QIGDTFHLSF S OR5B c.798G>T p.M26 SHLIAIFLFYITVIIMYIRPSSSHS[p.M266 SSHSIDTDK,SIDTDKIASV,YIRPSSSHSI,SSSHSIDTDK,RPSSS LUAD 17 6I I]IDTDKIASVFYTMIIPMLSPIVYTLR HSIDT,IDTDKIASVF OR5D c.706C>T p.R236 SSLIIILTSYMLIFTTIMKMRSASG[p.R23 KMRSASGCQ,SASGCQKTF,CQKTFSTCA,KMRSASGCQK,R GBM 13 C 6C]CQKTFSTCASHLTAITIFHGTILFLY SASGCQKTF,CQKTFSTCAS OR5D c.736C>A p.H246 VFIFVTVLKIRSVSGRHKAFSTWAS[p.H TWASNLTSI,KAFSTWASN,ASNLTSITI,SNLTSITIF,STWASN LUAD 14 N 246N]NLTSITIFHGTILFLYCVPNSKNSR LTSI,KAFSTWASNL,WASNLTSITI,ASNLTSITIF Q OR5D c.790C>A p.P264 VFSTCASHLTAITIFHGTILFLYCV[p.P26 FLYCVTNSK,CVTNSKNSR,LFLYCVTNSK LUAD 16 T 4T]TNSKNSRHTVKVASVFYTVVIPLLNP OR5D c.812C>A p.T271 LTAITIFHGTILFLYCVPNSKNSRH[p.T27 KVKVASVFY,RHKVKVASV,HKVKVASVF,NSKNSRHKVK,KV LUSC 18 K 1K]KVKVASVFYTVVIPMLNPLIYSLRNK KVASVFYT,RHKVKVASVF,HKVKVASVFY OR5F1 c.131G>T p.G44V DTLELQIILFLFFLVIYTLTVLGNL[p.G44V] VLGNLVMIL,TLTVLGNLV,TVLGNLVMI,LTVLGNLVM,YTLT LUAD VMILLIRIDSQLHTPMYFFLANLSFV VLGNLV,VLGNLVMILL,NLVMILLIRI,TLTVLGNLVM OR5J2 c.106G>T p.A36S EFILLGLTDHAELKAVLFVVFLVIY[p.A36 VVFLVIYSI,FLVIYSITL,LVIYSITLL,VIYSITLLR,YSITLLRNL,FV LUAD S]SITLLRNLGMILLIQITSKLHTPMYF VFLVIYSI,FLVIYSITLL,LVIYSITLLR,VFLVIYSITL,IYSITLLRNL OR5L1 c.824C>A p.T275 VFHGTVLSIYCRPSSGNSGDADKVA[p.T KVANVFYTV,ANVFYTVVI,DADKVANVF,DADKVANVFY,K LUAD N 275N]NVFYTVVIPMLNSVIYSLRNKDV VANVFYTVV,NVFYTVVIPM,GDADKVANVF,VANVFYTVVI KEA OR5M c.265de|A p.T89fs LSFVDVWFSSNVTPKMLENLLSDKK[p. LSDKKQLLM,LLSDKKQLL,KKQLLMLW,LSDKKQLLML,LLS STAD 3 T89fs]QLLMLVV* DKKQLLM OR5P c.299C>T p.A100 PNMLVNFLVERNTVSYLGCAIQLGS[p. QLGSVAFFA,GSVAFFATV,IQLGSVAFF,AIQLGSVAF,CAIQL GBM 2 V A100V]VAFFATVECVLLAAMAYDRFVA GSVA,IQLGSVAFFA,VAFFATVECV,CAIQLGSVAF,AIQLGS ICSP VAFF OR6C c.460_461i p.I154fs TTIMSNKVCNWLVISSWLAGFLIIF[p.I1 DYGPPTGFL,GFLIIFSPR,LIIFSPRDY,SPRDYGPPT,RDYGPP LUAD 65 nsT 54fs]SPRDYGPPTGFL* TGF,WLAGFLIIFS,AGFLIIFSPR,FLIIFSPRDY,RDYGPPTGFL OR6C c.280G>T p.G94 ISFTSVCIPRFLVTVVTGNRTISYN[p.G9 RTISYNWCV,SYNWCVAQL,YNWCVAQLF,NWCVAQLFF,S LUAD 75 W 4W]WCVAQLFFFIFLGVTEFYLLAAMSY YNWCVAQLF,YNWCVAQLFF,NWCVAQLFFF,RTISYNWCV D A,ISYNWCVAQL OR6K c.236C>A p.P79Q HLHTPMYTFISALSFLEIWYTTATI[p.P7 TIQKMLSSL,IQKMLSSLL,YTTATIQKM,TTATIQKML,ATIQK LUAD 2 9Q]QKMLSSLLSERSISFNGCLLQMYFF MLSSL,TIQKMLSSLL,IWYTTATIQK,WYTTATIQKM,YTTATI H QKML,IQKMLSSLLS OR6K c.931T>C p.F311 YLRFSATYSVFWDTAIAVTFVILAP[p.F31 VTFVILAPL,ILAPLFNPI,TFVILAPLF,APLFNPIIY,VILAPLFNPI, TGCT,THCA 6 L 1L]LFNPIIYSLKNKDMKEAIGRLFHYQ ILAPLFNPII,AVTFVILAPL,LFNPIIYSLK,VTFVILAPLF,LAPLF K NPIIY OR6N c.877C>T p.R293 LTLDRTLAIVYSVLTPMVNPIIYSL[p.R29 SLCNKEIIK,PIIYSLCNK,IYSLCNKEI,YSLCNKEII,IYSLCNKEI, GBM 2 C 3C]CNKEIIKAIKRTIFQKGDKASLAHL YSLCNKEIIK,IYSLCNKEII,CNKEIIKQIK,MVNPIIYSLC OR6V c.744de|C p.I248fs VLRIPSASSCQKAFSTCGSHLTLVF[p.I24 LTLVFMATV,TLVFMATVV,FMATVVPSF,FCMSGLAKL,GL HNSC 1 8fs]MATVVPSFCMSGLAKLTLCKSGRS AKLTLCK,SFCMSGLAK,GSHLTLVFM,VPSFCMSGL,MSGLA WPW* KLTL,TLCKSGRSW,CKSGRSWPW,HLTLVFMATV,LTLVFM ATW,FMATVVPSFC,VVPSFCMSGL,CMSGLAKLTL,PSFC MSGLAK,SGLAKLTLCK,VFMATVVPSF,MATVVPSFCM,LTL CKSGRSW OR7C c.311de|T p.F104fs PKMLLNILTQNKFITYAGCLSQIFF[p.F1 CLSQIFFSL,SQIFFSLHL,SLHLDAWTI,FFSLHLDAW,LHLDA KIRC 1 04fs]SLHLDAWTIYS* WTIY,FSLHLDAWTI,IFFSLHLDAW,SLHLDAWTIY,LSQIFFS LHL OR7C c.535de|T p.C179fs MGSLLETLTVLRLSFCTEMEIPHFF[p.C1 MEIPHFFVI,EMEIPHFFV,IPHFFVIYL,MEIPHFFVIY,IPHFFV STAD 1 79fs]VIYLKS* IYLK,TEMEIPHFFV,EMEIPHFFVI,EIPHFFVIYL OR7E c.21_22insT p.L7fs MSYFPILFFFF[p.L7fs]PQKVSELHRATE ILFFFFPQK,LFFFFPQK,ATESHRCLR,GSRTAAGPR,RTAAG PRAD 24 SHRCLRIPPPGTLRGSRTAAGPRWAVP PRWA,TAAGPRWAV,TLRGSRTAA,RATESHRCL,LRIPPPGT VHVPGHGAGEPAHHPGCQL* L,FPQKVSELH,ILFFFFPQKV,RTAAGPRWAV,PILFFFFPQK, FFFPQKVSEL,RATESHRCLR,CLRIPPPGTL,GTLRGSRTAA,R GSRTAAGPR,ELHRATESHR,GPRWAVPVHV,EPAHHPGCQ L,SELHRATESH,HRATESHRCL,GSRTAAGPRW,FPILFFFFP Q OR8D c.917G>T p.R306 IIPMLNPLIYSLRNKDVKNALKKMT[p.R ALKKMTMGR,KNALKKMTM,KKMTMGRQS,KMTMGRQS LUAD 2 M 306M]MGRQSS S,NALKKMTMGR,VKNALKKMTM,KKMTMGRQSS OR8H c.498G>T p.L166 CLALITGPYVIGFIDSFVNVVSMSR[p.L1 VSMSRFHFY,VVSMSRFHF,MSRFHFYDS,RFHFYDSNV,VN LUSC 2 F 66F]FHFYDSNVIHHFFCDTSPILALSCTD VVSMSRF,FHFYDSNVI,VVSMSRFHFY,RFHFYDSNVI,MSR FHFYDSN,FVNVVSMSRF,NVVSMSRFHF,SRFHFYDSNV,F HFYDSNVIH OR8J3 c.479C>T p.S160 VVSRRLCLLLVSLTYLYGFSTAIVV[p.S16 VVLPCIFSV,TAIVVLPCI,LPCIFSVSY,AIVVLPCIF,IVVLPCIFS LUSC L 0L]LPCIFSVSYCSSNIINHFYCDIAPLL V,VLPCIFSVSY,STAIVVLPCI,YGFSTAIVVL,TAIVVLPCIF OR8K c.705G>T p.K235 SLLIVLLSYLLILVAILRMNSAGRQ[p.K23 NSAGRQNAF,NAFSTCGAH,RQNAFSTCG,RMNSAGRQNA, LUSC 3 N 5N]NAFSTCGAHLTVVIVFYGTLLFMYV RQNAFSTCGA,MNSAGRQNAF,NAFSTCGAHL Q OR8S1 c.296C>T p.A99V SSVIVPKMLENLLSQRKTISVEGCL[p.A9 LVQVFFVFV,TISVEGCLV,CLVQVFFVF,VEGCLVQVF,VQVF CRC 9V]VQVFFVFVTAGTEACLLSGMAYDR FVFVT,CLVQVFFVFV,VQVFFVFVTA,KTISVEGCLV,GCLVQ HA VFFVF,EGCLVQVFFV,SVEGCLVQVF,VEGCLVQVFF OR9A c.865C>T p.R289 VEYNKIVSLLVSVLTPFLNPFIFTL[p.R28 FIFTLWNDK,FTLWNDKVK,LNPFIFTLW,FIFTLWNDKV,TL LUAD 2 W 9W]WNDKVKEALRDGMKRCCQLLKD* WNDKVKEA,FLNPFIFTLW OR9G c.506G>T p.R169 VAVSYCGGFINSSIITKKTFSFNFC[p.R16 KTFSFNFCL,SFNFCLENI,FNFCLENII,LENIIDDFF,FSFNFCLE LUAD 9 L 9L]LENIIDDFFCDLLPLVELACGEKGGY NI,SFNFCLENII,KTFSFNFCLE,KKTFSFNFCL OSBP c.2163G>C p.Q721 FSELALTLNAWESGTAPTDSRLRPD[p. RLRPDHRLM,DSRLRPDHR,RLRPDHRLME,SRLRPDHRLM CESC H Q721H]HRLMENGRWDEANAEKQRLE EKQRLS OSBP c.1881_188 p.H627fs ETFELDRLDDMGLRSLCEQVSHHPP[p. VLQAWLEPL,ALRVLQAWL,KIHLHHAAR,HAARCHPLR,AA STAD 2 2insC H627fs]LSCALRVLQAWLEPLAGDHHL RCHPLRI,HLNCSQHHR,SQHHRGQAL,HHAARCHPL,EQVS QQVPGKIHLHHAARCHPLRIPGQWESL HHPPL,CALRVLQAW,LQAWLEPLA,LQQVPGKIH,QQVPG RVEEEHLNCSQHHRGQALDRPVRGHR KIHL,GKIHLHHAA,GQWESLRVE,EPLAGDHHL,HPLRIPGQ DCEP* W,RVLQAWLEPL,VLQAWLEPLA,KIHLHHAARC,HHAARC HPLR,CEQVSHHPPL,SHHPPLSCAL,LQAWLEPLAG,LQQVP GKIHL,QQVPGKIHLH,LHHAARCHPL,LRIPGQWESL,WESL RVEEEH,LEPLAGDHHL,HPPLSCALRV,IPGQWESLRV OSBPL c.1730G>A p.R577 SEDNTSVADNISRQILNGELTGGAF[p.R FQNGRRACL,LTGGAFQNGR UCEC 6 Q 577Q]QNGRRACLPAPCPDTSNINLWN ILRN OSTN c.344G>A p.R115 PLDRLSAGSVDHKGKQRKVVDHPKR[p. RQFGIPMDR,PKRQFGIPM,RQFGIPMDRI,HPKRQFGIPM, CRC Q R115Q]QFGIPMDRIGRNRLSNSRG KVVDHPKRQF OTOF c.1163C>T p.T388 DDISSGLKGYVKCDVAWGKGDNIK[p. KGDNIKMPHK BRCA M T388M]MPHKANETDEDDIEGNLLLPE GVPPE OTOF c.3910G>A p.E130 KLETMVKLDATSEAVVKVDVAEEEK[p. KVDVAEEEKK STAD 4K E1304K]KKKKKKKGTAEEPEEEEPDES MLDWW OTOL c.1291G>A p.V431I VAQNKKQFKSRETLYGQEIDQASLL[p.V QASLLIILK,DQASLLII,DQASLLIIL,QEIDQASLLI,DQASLLIIL CRC 1 431I]IILKLSAGDQVWLEVSKDWNGVY VSA OTOP c.310_318d p.LLW1 AWAVHAAGVSKSDLLCFLTALMLLQ[p. MLLQMLWYV,LQMLWYVGR,LMLLQMLWY,LTALMLLQ ACC 1 e|CTGCTGT 04de| LLW104de|]MLWYVGRSSAHRRLFRLK M,ALMLLQMLW,FLTALMLLQM,LMLLQMLWYV,ALMLL GG DTHAGAGWLRGSITLF QMLWY,LLQMLWYVGR,TALMLLQMLW OTUD c.830G>T p.R277I VQNLEAENYNIESAIIAVLRMNQGK[p. RMNQGKINNA,GKINNAEENL CRC 3 R277I]INNAEENLEPSGRVLKQCGPLW EEGG OTUD c.2726C>T p.T909I ALASIPPVAEGKAHPPTQILNRERE[p.T9 ILNREREIV,REREIVPVE,LNREREIVPV,TQILNREREI,REREI BLCA,PRAD, 4 09I]IVPVELEPKRTIQSLKEKTEKVKDPK VPVEL,REIVPVELEP THCA OTUD c.458_460d p.A153 VADEDNSEISDSEDDSCKSKTAAAA[p.A KSKTAAAAD,KSKTAAAADV,TAAAADVNGF PRAD 4 e|CTG de| 153de|]DVNGFKPLSGNEQLKNNGNST SLPLSRK OTX2 c.130de|C p.R44fs TSGMDLLHPSVGYPGPWASCPAATP[p. RGRRSLGRS,SAGRGRRSL,AGRGRRSLGR,CPAATPGNSA,N STAD R44fs]GNSAGRGRRSLGRS* SAGRGRRSL OXR1 c.364G>A p.E122 GTIEYTVESRDSLNSIALKFDTTPN[p.E1 KLVQLNKLF,ALKFDTTPNK,DTTPNKLVQL,LKFDTTPNKL,N UCEC K 22K]KLVQLNKLFSRAVVTGQVLYVPDP KLVQLNKLF EY P2RX1 c.58de|C p.R20fs MARRFQEELAAFLFEYDTP[p.R20fs]A FLFEYDTPA,DTPAWCWCV,TPAWCWCVI,WCVIRRWAL,F STAD WCWCVIRRWALSSD* LFEYDTPAW,AWCWCVIRRW,CWCVIRRWAL,TPAWCWC VIR,DTPAWCWCVI,FEYDTPAWCW P2RX7 c.425C>A p.P142 RLCPEYPTRRTLCSSDRGCKKGWMD[p. WMDQQSKGI,KGWMDQQSK LUAD Q P142Q]QQSKGIQTGRCVVYEGNQKTC EVSAW PABP c.1223A>T p.Y408 MQRMASVRAVPNPVINPYQPAPPSG[p. YQPAPPSGF,QPAPPSGFF,PYQPAPPSGF,YQPAPPSGFF,Q KIRC C1 F Y408F]FFMAAIPQTQNRAAYYPPSQI PAPPSGFFM,APPSGFFMAA,PPSGFFMAAI AQLRP PABP c.280C>T p.R94C LDTMNFDVIKGKPVRIMWSQRDPSL[p. SQRDPSLCKXK,CSGVGNIF,SLCKSGVGN,WSQRDPSLCK,LC DLBCL C1 R94C]CKSGVGNIFIKNLDKSIDNKALYD KSGVGNIF TF PABP c.467_468i p.E156f DENGSKGYGFVHFETQEAAERAIEK[p.E AERAIEKNEW KIRC C1 nsG s 156fs]NEWNAPK* PABP c.541G>A p.A181 EKMNGMLLNDRKVFVGRFKSRKERE[p. SRKERETEL,KERETELGA,RETELGARA,KSRKERETEL,TELG KIRC C1 T A181T]TELGARAKEFTNVYIKNFGED ARAKEF MDDER PABP c.761_762i p.K254f KSKGFGFVSFERHEDAQKAVDEMNG[p. NLCWSSSEK,KTNLCWSSS,AQWKTNLCW,DEMNGNGAQ, CLL C1 nsT s K254fs]NGAQWKTNLCWSSSEKGGTA TNLCWSSSEK,AQWKTNLCWS,DEMNGNGAQW DGT* PABP c.999de|A p.K333f LRKEFSPFGTITSAKVMMEGGRSKG[p. VLYVSPPQK,RSKGLVLYV,GRSKGLVLY,MMEGGRSKGL,LV KIRC C1 s K333fs]LVLYVSPPQKKPLKQLQK* LYVSPPQK,VLYVSPPQKK,RSKGLVLYVS,VSPPQKKPLK,GG RSKGLVLY PABP c.975_979d p.V325 LDDGIDDERLRKAFSPFGTITSAKV[p.V3 RVWFCMFLL,KVGRWSQQR,RWSQQRVWF,QQRVWFC TGCT C3 e|TATGA fs 25fs]GRWSQQRVWFCMFLLPRRSH* MF,TITSAKVGR,WFCMFLLPR,GRWSQQRVW,SQQRVWF CM,GTITSAKVGR,VWFCMFLLPR,SQQRVWFCMF,KVGR WSQQRV,QQRVWFCMFL,WFCMFLLPRR,VGRWSQQRV W,GRWSQQRVWF,WSQQRVWFCM,CMFLLPRRSH PABP c.997de|A p.K333f LRKAFSPFGTITSAKVMMEGGRSKG[p. VLYVSPPQK,RSKGLVLYV,GRSKGLVLY,MMEGGRSKGL,LV BLCA C3 s K333fs]LVLYVSPPQKKPLKQLQK* LYVSPPQK,VLYVSPPQKK,RSKGLVLYVS,VSPPQKKPLK,GG RSKGLVLY PACSI c.1075G>A p.E359 AVESTSQAGDRGSVSSYDRGQPYAT[p. RGQPYATKW HNSC N1 K E359K]KWSDDESGNPFGGSETNGGAN PFEDD PACSI c.993G>C p.Q331 ADLNRTLSRREKKKATDGVTLTGIN[p.Q INHTGDQSL,HTGDQSLPSK BRCA N2 H 331H]HTGDQSLPSKPSSTLNVPSNPAQ SAQ PADI2 c.340A>C p.T114 SSDKVTVNYYDEEGSIPIDQAGLFL[p.T1 GLFLPAIEI,FLPAIEISL,DQAGLFLPA,LFLPAIEISL,DQAGLFL MM P 14P]PAIEISLDVDADRDGVVEKNNPKK PAI,LPAIEISLDV,IDQAGLFLPA AS PAFA c.904de|A p.K302f VECISWAPESSYSSISEATGSETKK[p.K3 RLLRCGMSV,GMSVLACAL,LLRCGMSVL,SETKKVVNL,RLL STAD H1B1 s 02fs]VVNLGHSCCLDPETRLLRCGMSVL RCGMSVL,LLRCGMSVLA,CGMSVLACAL ACAL* PALB2 c.839de|A p.N280 DSGSSQHLEHIPPKGSSELTTHDLK[p.N LKTLDLLHL,SELTTHDLKT STAD fs 280fs]TLDLLHL* PALLD c.2986G>A p.A996 DSAHKMLVRENGVHSLIIEPVTSRD[p.A VTSRDTGIY,RDTGIYTCI,PVTSRDTGIY KIRC T 996T]TGIYTCIATNRAGQNSFSLELVVA AK PALM c.3213_321 p.1075_ KAVSKTSRDGAEQQGPEATVEEAEA[p. EAEAEAAAF,VEEAEAEAA,AEAEAAAFG,EEAEAEAAAF,AE KIRC 2- 4insGAAGC 1076i 1075_1076insEA]EAAAFGSEKPQSMF AEAAAFGS,VEEAEAEAAA AKAP T nsEA EPPQVSSPVQEKRDVLP 2 PALM2- c.3354_335 p.G111 VQEKRDVLPKILPAEDRALRERGPP[p.G RERGPPPAT,ALRERGPPPA,RERGPPPATA KIRC AKAP 5insC 8fs 1118fs]PATASCAAQWPD* 2 PALM c.895G>A p.A299 KLEMVHKSRKDHSSGNPGQQAQAPS[p. STAGPEANL,APSTAGPEA,GQQAQAPST,QQAQAPSTA,G BRCA 2- T A299T]TAGPEANLDQPVTMIFMGY QQAQAPSTA,QQAQAPSTAG AKAP QNIEDEE 2 PAMR c.302de|G p.G101 CDSCLIHPGCTIFENCKSCRNGSWG[p. WGVPWMTSM,RNGSWGVPW,KSCRNGSWGV,CRNGSW STAD 1 fs G101fs]VPWMTSM* GVPW,RNGSWGVPWM,SWGVPWMTSM PANK c.1199de|A p.K400f DSVGFNGKPECYYFENPTNPELCQK[p. TLCCWLTWA,WLTWAQVSA,RTALITHTL,HTLCCWLTW,C STAD 1 s K400fs]SRTALITHTLCCWLTWAQVSAF QKSRTALI,KSRTALITH,LTWAQVSAF,LCQKSRTAL,LITHTLC * CWL,KSRTALITHT,HTLCCWLTWA,ELCQKSRTAL,WLTWA QVSAF,SRTALITHTL,ALITHTLCCW PANK c.1251de|T p.T417fs VSILAVYSKDNYKRVTGTSLGGGTF[p.T SLGGGTFLV,FLVSAVFLL,AVFLLAVPL,LLKWHLVEI,LVSAVF PRAD 2 417fs]LVSAVFLLAVPLLKKLLKWHLVEI LLA,FLLAVPLLK,LLAVPLLKK,TFLVSAVFL,VFLLAVPLL,GTFL APKWIN* VSAVF,VSAVFLLAV,LKWHLVEIA,HLVEIAPKW,FLVSAVFLL A,LVSAVFLLAV,AVFLLAVPLL,LLAVPLLKKL,KLLKWHLVEI,L LKKLLKWHL,LLKWHLVEIA,HLVEIAPKWI,FLLAVPLLKK,VF LLAVPLLK,AVPLLKKLLK,TFLVSAVFLL,GTFLVSAVFL,KWHL VEIAPK,TSLGGGTFLV,SAVFLLAVPL,GGTFLVSAVF,VPLLK KLLKW PANK c.377G>C p.G126 AAEEARRNPTLGGLLGRQRLLLRMG[p. LLRMGAGRL,RMGAGRLGA,LLLRMGAGR,GAGRLGAPM, ACC 2 A G126A]AGRLGAPMERHGRASATSVSS RQRLLLRMGA,RLLLRMGAGR,AGRLGAPMER,MGAGRLG AGEQA APM,LRMGAGRLGA PANK c.779G>T p.R260I LEMASKGDSTQADKLVRDIYGGDYE[p. IYGGDYEIF,IFGLPGWAV,DIYGGDYEI,EIFGLPGWA,YEIFG CRC 3 R260I]IFGLPGWAVASSFGNMIYKEKRE LPGW,EIFGLPGWAV,DIYGGDYEIF,RDIYGGDYEI,YEIFGLP SVS GWA PAOX c.319C>T p.H107 QLAAEYGLLGEKELSQENQLVETGG[p. QLVETGGYV,NQLVETGGY,YVGLPSVSY,VETGGYVGL,YVG CESC Y H107Y]YVGLPSVSYASSGASVSLQLVAE LPSVSYA,GYVGLPSVSY MAT PAPD c.675_676i p.C225f SLNGFGTRSSDGDLCLWKEEPCFF[p.C KEEPCFFSG STAD 4 nsT s 225fs]SGKSED* PAPP c.2749C>A p.P917 QYVHTASSRRVCDSSGYWTPEEAVG[p. EEAVGTPDV LUAD A2 T P917T]TPDVDQPCEPSLQAWSPEVHLY HMNM PAPP c.5049de|C p.I1683 NSVEYKCEQGYGIGAVCSPLCVIPP[p.I1 SPLCVIPPV,CSPLCVIPPV STAD A2 fs 683fs]VTP* PAPP c.5117C>A p.P170 CVIPPSDPVMLPENITADTLEHWME[p. TLEHWMEHV,MEHVKVQSI,WMEHVKVQSI,TLEHWMEH LUAD A2 6H P1706H]HVKVQSIVCTGRRQWHPDPV VK,DTLEHWMEHV,MEHVKVQSIV,LEHWMEHVKV LVHCIQ PARD c.252_253i p.G84fs TDAHGDLLPLTNDDSLHRALASGPP[p. ALASGPPAT,RALASGPPA,ALASGPPATA,RALASGPPAT,H KIRC 6A nsC G84fs]ATAPTGAEAGRS* RALASGPPA PARG c.1750G>A p.A584 KYNVAYSKKWDFTALIDFWDKVLEE[p. EETEAQHLY,LEETEAQHL,TEAQHLYQS,LEETEAQHLY,TEA KIRP,PRAD T A584T]TEAQHLYQSILPDMVKIALCLPN QHLYQSI ICT PARP1 c.1381de|A p.K461f PSLKTVKVVIFQPELLNIFYDSMKK[p.K4 SMKKETSLH,DSMKKETSL,MKKETSLHH,SMKKETSLHH STAD 5 s 61fs]ETSLHH* PARP4 c.2541de|A p.K847f SSLDSSGFSLHIGLSAAYLPRMWVE[p.K RMWVENIQK,IQKKKARLA,KARLACLSF,LPRMWVENI,NPI STAD s 847fs]NIQKKKARLACLSFNPISMSTSLT SMSTSL,NIQKKKARL,KKKARLACL,LACLSFNPI,CLSFNPIS * M,YLPRMWVENI,RLACLSFNPI,RMWVENIQKK,KARLACL SFN,KKARLACLSF,ACLSFNPISM PASD1 c.685_687d p.A236 SSQGQRGHTSMKAVYVEPAAAAAAA[p. EPAAAAAAAI GBM e|GCT de| A236de|]ISDDQIDIAEVEQYGPQEN VHMFVDSDS PASK c.185C>T p.T62I PSRSFSSAHRHLSRRNGLSRLCQSR[p.T RLCQSRIAL,LSRLCQSRI,GLSRLCQSRI,LSRLCQSRIA,SRLCQ KIRC 62I]IALSEDRWSSYCLSSLAAQNICTSKL SRIAL PAX2 c.1183de|C p.P395f YSHPQYTAYNEAWRFSNPALLMPPP[p. PVRPCRCCR,MPPPVRPCR,RPCRCCRCL,LLMPPPVRPC,L STAD s P395fs]VRPCRCCRCL* MPPPVRPCR,NPALLMPPPV PAX3 c.1271C>T p.T424 HGGVPHQPQTDYALSPLTGGLEPTT[p. MVSASCSQR,LEPTTMVSA,MVSASCSQRL,TMVSASCSQR CRC M T424M]MVSASCSQRLDHMKSLDSLPT SQSYC PAX3 c.590C>T p.S197 LERKEAEESEKKAKHSIDGILSERA[p.S1 SERALAPQS BLCA L 97L]LAPQSDEGSDIDSEPDLPLKRKQRR S PAX6 c.1124de|C p.P375fs QTSSYSCMLPTSPSVNGRSYDTYTP[p.P RSYDTYTPH,SYDTYTPHI,DTYTPHICR,RSYDTYTPHI STAD 375fs]HICRHT* PBLD c.164C>A p.P55Q LDEDMHQKIAREMNLSETAFIRKLH[p. KLHQTDNFA,RKLHQTDNF,IRKLHQTDNF,HQTDNFAQSS LUAD P55Q]QTDNFAQSSCFGLRWFTPASEV PLCG PBX2 c.208G>A p.E70K PGGRGKQDIGDILQQIMTITDQSLD[p. TITDQSLDK,QSLDKAQAK,SLDKAQAKK,KAQAKKHAL,MTI BLCA E70K]KAQAKKHALNCHRMKPALFSVL TDQSLDK,QSLDKAQAKK CEIK PBX2 c.785A>T p.Y262 LRSRFLDARRKRRNFSKQATEVLNE[p.Y QATEVLNEF,TEVLNEFFY,NEFFYSHLS,ATEVLNEFFY,VLNE KIRP,LUSC, F 262F]FFYSHLSNPYPSEEAKEELAKKCGI FFYSHL,KQATEVLNEF,FFYSHLSNPY,NEFFYSHLSN TGCT T PBXIP c.2186_218 p.H729 KKDKHSQSPRAAGPREGHSHSHHHH[p. HSHSHHHHR BLCA 1 8de|ACC de| H729de|]RG* PCBP1 c.305T>A p.L102 DKLEEDINSSMTNSTAASRPPVTLR[p.L RPPVTLRQV,RQVVPATQC,RPPVTLRQVV,RQVVPATQCG CRC Q 102Q]QVVPATQCGSLIGKGGCKIKEIRE ST PCCA c.689G>A p.R230 AVRIAREIGYPVMIKASAGGGGKGM[p. HIAWDDEETR STAD H R230H]HIAWDDEETRDGFRLSSQEAAS SFGD PCDH c.1429G>A p.V477 QVSDVNDNAPRFSQPVYDVYVTENN[p. NMPGAYIYA,TENNMPGAY,NNMPGAYIY,MPGAYIYAV,V CRC 10 M V477M]MPGAYIYAVSATDRDEGANA TENNMPGAY,YVTENNMPGA,NMPGAYIYAV,YDVYVTEN QLAYSI NM,MPGAYIYAVS,TENNMPGAYI PCDH c.1759C>A p.R587 ILIVDQNDNAPAIVAPLPGRNGTPA[p.R GTPASEVLPR,RNGTPASEVL LUAD 10 S 587S]SEVLPRSAEPGYLLTRVAAVDAD DGE PCDH c.2956G>T p.V986 SDGRQAADYRSNLHVPGMDSVPDTE[p. TELFETPEA,GMDSVPDTEL,MDSVPDTELF LUAD 10 L V986L]LFETPEAQPGAERSFSTFGKEK ALHS PCDH c.354_355i p.N118 EVFLENPLELFQVEIEVLDINDNPP[p.N1 VLDINDNPPL,LDINDNPPLF STAD 10 nsC fs 18fs]LFPGARPDGGNL* PCDH c.673_674i p.P225f TAVDGGGGGGVGEGGGGGGGAGLPP AAHRHGPTH,GPTHHPSAGL,RHGPTHHPSA STAD 10 nsC s [p.P225fs]PAAAHRHGPTHHPSAGLQ* PCDH c.1457C>T p.T486 DNAPVFTQSFVTVSIPENNSPGIQL[p.T IQLMKVSAM,QLMKVSAMDA GBM 11X M 486M]MKVSAMDADSGPNAKINYLLG PDAPP PCDH c.3029G>T p.R101 SSDPYSVSDCGYPVTTFEVPVSVHT[p.R SVHTIPPMK,EVPVSVHTI,HTIPPMKEV,VSVHTIPPM,VSVH LUAD 11X 0I 1010I]IPPMKEVVRSCTPMKESTTMEI TIPPMK,TIPPMKEVVR,HTIPPMKEVV,FEVPVSVHTI WIHP PCDH c.4655G>T p.R155 DDLSAHNPLYKENISQVSTNSDISQ[p.R DISQITDFV,QITDFVDPF,SDISQITDF,SQITDFVDPF CRC 15 2I 1552I]ITDFVDPFSPKIQAKSKSLRGPRE KI PCDH c.5138G>T p.C171 VELKSEPNVISSPAECSLELSPSRP[p.C17 ELSPSRPFV,FVLHSSLSR,RPFVLHSSL,LELSPSRPF,FVLHSSL KIRC 15 3F 13F]FVLHSSLSRRETPICMLPIETERNIF SRR,SLELSPSRPF,LELSPSRPFV PCDH c.1588G>A p.E530 YVSINPNSGDIYALRSFNHEQTKAF[p.E QTKAFKFKV,KAFKFKVLA,AFKFKVLAK,TKAFKFKVL,HEQT UCEC 19 K 530K]KFKVLAKDGGLPSLQSNATVRVII KAFKF,KAFKFKVLAK,QTKAFKFKVL LD PCDH c.856C>T p.R286 NASDPDEGTNGQVVYSFYGYVNDRT[p. YVNDRTCEL,YVNDRTCELF BRCA 19 C R286C]CELFQIDPHSGLVTVTGALDYE EGHV PCDH c.1555G>A p.A519 LVERRVGERALSNYVSVHAESGKVY[p. AESGKVYTL,GKVYTLQPL,TLQPLDHEEL,KVYTLQPLDH,SG CRC AC2 T A519T]TLQPLDHEELELLQFQVSARDA KVYTLQPL,HAESGKVYTL GVPP PCDH c.2207C>T p.A736 ALSTVSFIFLLTIIILSIIKCYRYT[p.A736V] IIKCYRYTV,YTVYGTACC,IKCYRYTVY,YRYTVYGTA,SIIKCYR CRC AC2 V VYGTACCGGFCGVRERSPAELYKQAN YTV,VYGTACCGGF,IIKCYRYTVY,CYRYTVYGTA,YRYTVYGT AC PCDH c.2225C>T p.A742 TALRCSAAPTEGACGPVKPTLVCSS[p.A SSVVGSWSY,KPTLVCSSV,CSSVVGSWSY,KPTLVCSSVV,LV LUAD AC2 V 742V]VVGSWSYSQQRRQRVCSGEGLP CSSVVGSW KADL PCDH c.414G>T p.K138 PLQVFHVDVEVKDINDNPPVFPATQ[p. VFPATQNNL,NNLFIAESR,FPATQNNLF,VFPATQNNLF,FP UCEC AC2 N K138N]NNLFIAESRPLDSRFPLEGASDA ATQNNLFI DIG PCDH c.467C>T p.A156 RFSRQEQRLFILESRMPDSRFPLEG[p.A DSRFPLEGV,FPLEGVSDL CRC AC2 V 156V]VSDLDIGANAQLRYRLNPNEYFD LDV PCDH c.568G>A p.E190 NALLSYKLSSSEFFFLDIQANDELS[p.E19 ELSKSLSLV,KSLSLVLGK,LSKSLSLVL,DELSKSLSL,DELSKSLS CRC AC2 K 0K]KSLSLVLGKSLDREETAEVNLLLVAT LV PCDH c.796G>A p.A266 AFERTIYKVRLLENAPNGTLVVTVN[p.A NTTDLDEGV,TTDLDEGVNK CRC AC2 T 266T]TTDLDEGVNKDIAYSFNTDMSAD ILS PCDH c.811G>A p.E271 SYKVVLSENVQNDTRVIQLNASDPD[p. QLNASDPDK,KGLNGEISY CRC AC2 K E271K]KGLNGEISYGIKMILPVSEKCMF SIN PCDH c.1704C>G p.N568 SSQVTVRVVVLDDNDNRPMILYPLQ[p. ILYPLQKGT,PMILYPLQK,ILYPLQKGTL,RPMILYPLQK,YPLQ LUSC B1 K N568K]KGTLPCNDLVPRSAEAGYLVTK KGTLPC VVAV PCDH c.865C>T p.R289 VSAWDLDSGTNSELSYTFSHASEDI[p.R ASEDICKTF,FSHASEDICK,HASEDICKTF,SEDICKTFEI UCEC B12 C 289C]CKTFEINQKSGDITLTAPLDFEAIE S PCDH c.662C>T p.P221 VLDKALDREEEAELRLTLTALDGGS[p.P LPRSGTAQV,SLPRSGTAQV,TALDGGSLPR,LPRSGTAQVY GBM B13 L 221L]LPRSGTAQVYIEVLDVNDNAPEFE QP PCDH c.763_764C p.P255 LIMDINDNAPEFVHTPYGVQVLENS[p. FLDSPIVRV,SFLDSPIVR,NSFLDSPIV,GVQVLENSF,VQVLE TGCT B4 C>TT F P255F]FLDSPIVRVLARDIDAGNFGSVS NSFL,FLDSPIVRVL,NSFLDSPIVR,YGVQVLENSF,LENSFLDS YGLF PI PCDH c.151G>T p.D51Y AGSEAVRYSIPEETESGYSVANLAK[p.D YSVANLAKY,YLGLGVGEL,AKYLGLGVG,NLAKYLGLGV,YLG CRC B5 51Y]YLGLGVGELATRGARMHYKGNKE LGVGELA,KYLGLGVGEL,GYSVANLAKY,YSVANLAKYL LLQ PCDH c.1945C>T p.P649 RTARLLSERDAAKHRLVVLVKDNGE[p. SPRSATATL,GESPRSATA,LVKDNGESPR,ESPRSATATL,GES LUAD B5 S P649S]SPRSATATLHVLLVDGFSQPYLP PRSATAT LPE PCDH c.703G>A p.D235 RLTLTALDGGSPPRSGTAQVYIEVV[p.D QVYIEVVNV,EVVNVNDNA,NVNDNAPEF,AQVYIEVVNV,V CRC B8 N 235N]NVNDNAPEFEQPFYRVQISEDSP NVNDNAPEF,IEVVNVNDNA ISF PCDH c.1796G>T p.G599 GVELAPRSAERGYLVTKVVAVDRDS[p. SVQNAWLSY,VQNAWLSYR,VVAVDRDSV,VQNAWLSYRL, KIRC GC5 V G599V]VQNAWLSYRLLKASEPGLFSVG SVQNAWLSYR,DSVQNAWLSY,VDRDSVQNAW LHTG PCDH c.1984G>A p.V662 ALKQSLVVAVQDHGQPPLSATVTLT[p. LSATVTLTM,ATVTLTMAV,LTMAVADSI,TVTLTMAVA,MA CRC GC5 M V662M]MAVADSIPEVLADLGSLEPSD VADSIPEV,TLTMAVADSI,SATVTLTMAV,PLSATVTLTM GPYNY PCDH c.1990G>A p.D664 RLLVAVRDGGQPPLSATATLHLVFA[p. VFANSLQEV,LHLVFANSL,FANSLQEVL,LVFANSLQEV,TLH BRCA GC5 N D664N]NSLQEVLPDITDRPDPSDLQAE LVFANSL,VFANSLQEVL LQFY PCDH c.2051C>A p.P684 TVTVAVADRIPDILADLGSIKTPID[p.P6 HEDLDLTLY,IDHEDLDLTL,TPIDHEDLDL,HEDLDLTLYL LUAD GC5 H 84H]HEDLDLTLYLVVAVAAVSCVFLAF VI PCDH c.208G>A p.A70T SVVGNLAKDLGLSVLDVSARKLRVS[p.A SARKLRVST,RKLRVSTEK,KLRVSTEKL,STEKLHFSV,RVSTEK UCEC GC5 70T]TEKLHFSVDAESGDLLVKNRIDREQ LHF,KLRVSTEKLH,VSTEKLHFSV,RKLRVSTEKL,LRVSTEKLH I F,TEKLHFSVDA PCDH c.36G>T p.K12N MAALQKLPHCR[p.K12N]NLVLLCFLLA KLPHCRNLV,NLVLLCFLL,LPHCRNLVL,QKLPHCRNL,KLPH LUAD GC5 TLWEARAGQIRYSVRE CRNLVL,LPHCRNLVLL,LQKLPHCRNL,HCRNLVLLCF PCDH c.866C>T p.S289 LTATDPDEGINGKLTYSFRNEEEKI[p.S2 EEEKILETF,NEEEKILETF,LETFQLDSNL CRC GC5 L 89L]LETFQLDSNLGEISTLQSLDYEESRF PCDH c.877C>T p.R293 DPDEGANGEVTYSFHNVDHRVAQIF[p. CLDSYTGEI,AQIFCLDSY,HRVAQIFCL,VAQIFCLDSY,AQIFC SKCM GC5 C R293C]CLDSYTGEISNKEPLDFEEYKMY LDSYT SME PCGF3 c.189de|C p.H63fs SCLVKYLEENNTCPTCRIVIHQSHP[p.H6 ILFTNWYQA,FTNWYQASK,TSVMTEPCK,HQSHPCSTS,QS STAD 3fs]CSTSVMTEPCKILFTNWYQASKKRK HPCSTSV,SHPCSTSVM,VMTEPCKIL,MTEPCKILF,CKILFTN * WY,KILFTNWYQA,HQSHPCSTSV,ILFTNWYQAS,FTNWYQ ASKK,STSVMTEPCK,VMTEPCKILF,LFTNWYQASK,QSHPC STSVM,EPCKILFTNW PCLO c.11836C>A p.P394 PYQTQPTFQAVATMSFTPQVQPTPT[p. PTPTTQPSY,TPTTQPSYQL,QPTPTTQPSY LUAD 6T P3946T]TQPSYQLPSQMMVIQQKPR QTTLYLE PCLO c.12397C>T p.R413 VKAEEDPMEDPYELKLLKHQIKQEF[p.R HQIKQEFCR,QEFCRGTES,QEFCRGTESL SKCM 3C 4133C]CRGTESLDHLAGLSHYYHADTS YRHF PCMT c.812G>T p.R271 LARIYIRRTLRNFINDEMQAKGIPQ[p.R MQAKGIPQM,GIPQMAPPK,MAPPKRKRK,QMAPPKRKR, LUAD D1 M 271M]MAPPKRKRKRVKQRINTYVFVG MQAKGIPQMA,KGIPQMAPPK,QMAPPKRKRK,MAPPKR NQLI KRKR,EMQAKGIPQM PCMT c.842T>C p.V281 RNFINDEMQAKGIPQRAPPKRKRKR[p. RAKQRINTY,RAKQRINTYV,KRAKQRINTY,AKQRINTYVF TGCT D1 A V281A]AKQRINTYVFVGNQLIPQPLDS EEDE PCNXL c.404G>A p.R135 GEHITNHRNPSNNRQIHNGKKEEAS[p. SQNLSTPPL,KKEEASQNL,SQNLSTPPLR,GKKEEASQNL,AS CRC 2 Q R135Q]QNLSTPPLRCSSRGQSITSHHSS QNLSTPPL,KEEASQNLST GPL PCOLC c.1043C>T p.A348 ITTITRDGSLHATVSIINIYKEGNL[p.A34 NIYKEGNLV,IYKEGNLVI,LVIQQAGKNM,KEGNLVIQQA CRC E2 V 8V]VIQQAGKNMSARLTVVCKQCPLLR RG PCOLC c.260G>A p.R87H KITVPEGKVVVLNFRFIDLESDNLC[p.R8 LESDNLCHY,CHYDFVDVY,SDNLCHYDF,ESDNLCHYDF,NL CRC E2 7H]HYDFVDVYNGHANGQRIGRFCGTF CHYDFVDV,LCHYDFVDVY RP PCP4L c.191A>G p.K64R DLTAPETEKAALAIQGKFRRFQKRK[p.K KFRRFQKRKR TGCT 1 64R]RDPSS* PDE4B c.1250C>T p.S417 MMTLEDHYHSDVAYHNSLHAADVAQ[p. HAADVAQLT,DVAQLTHVL,LHAADVAQL,AQLTHVLLS,SL CRC L S417L]LTHVLLSTPALDAVFTDLEILAA HAADVAQL,DVAQLTHVLI,LTHVLLSTPA,HAADVAQLTH, IFA ADVAQLTHVL,AQLTHVLLST PDGF c.685G>A p.E229 NVYALKATSELDLEMEALKTVYKSG[p.E KTIVVTCAV,TVYKSGKTI,YKSGKTIVV,ALKTVYKSGK,KTIVV GBM RA K 229K]KTIVVTCAVFNNEVVDLQWTYP TCAVF,KTVYKSGKTI,TVYKSGKTIV,YKSGKTIVVT GEVK PDGF c.1949C>T p.S650 SQATMKVAVKMLKSTARSSEKQALM[p. KQALMLELK,EKQALMLEL,ALMLELKIM,LELKIMSHL,MLEL GBM RB L S650L]LELKIMSHLGPHLNVVNLLGAC KIMSHL,RSSEKQALML,SEKQALMLEL,KQALMLELKI,LMLE TKGG LKIMSH PDIA6 c.168T>G p.N56K PCSPTSPAHSLSRKSPIMYPSTTMA[p.N TMAKAPGLV,MYPSTTMAK,TTMAKAPGL,YPSTTMAKA,T TGCT 56K]KAPGLVSCTFFLAVNGLYSSSDDVI TMAKAPGLV,IMYPSTTMAK,MYPSTTMAKA,KAPGLVSCT E F PDILT c.1498G>A p.E500 LYKGEHTLKGFSDFLESHIKTKIED[p.E50 HIKTKIEDK,IEDKDELLSV CESC K 0K]KDELLSVEQNEVIEEEVLAEEKEVPM PDPR c.2377G>T p.G793 TMFILDDHDSDLDLWPWWGEPIYRN[p. EPIYRNWQY,WQYVGKTTS,WWGEPIYRNW,IYRNWQYV LUAD W G793W]WQYVGKTTSSAYSYSLERHV GK,EPIYRNWQYV,WQYVGKTTSS CLGFVH PDS5A c.3927G>C p.L130 KNDDLNKPINKGRKRAAVGQESPGG[p. QESPGGFEA,GQESPGGFEA TGCT 9F L1309F]FEAGNAKAPKLQDLAKKAAP AERQID PDYN c.571G>T p.G191 EDPKEQVKRYGGFLRKYPKRSSEVA[p.G YPKRSSEVAW,VAWEGDGDSM LUAD W 191W]WEGDGDSMGHEDLYKRYGGFL RRIRP PDZD c.1693C>A p.R565 RKHSLPQLLDSSSASQEYHIVKKST[p.R5 IVKKSTSSL,TSSLSTTQV,KKSTSSLST,HIVKKSTSSL,STSSLST LUAD 2 S 65S]SSLSTTQVESPWRLIRPSVISIIGLY TQV,IVKKSTSSLS,KKSTSSLSTT PDZD c.302_303i p.R101fs DTETVGLSFGNIPVFGDYGEKRRGG[p. REEWEGPTA,EEQPSREEW,EEWEGPTAG,EENPPGSCA STAD 2 nsG R101fs]QEEENPPGSCAGCGLHLGDRA EEEQPSREEWEGPTAG* PELI2 c.589de|G p.G197 AKWKNPDGHMDGLTTNGVLVMHPR RTAPSLTCV,QMGFFILQL,VLVMHPRGA,MGFFILQLR,GAR STAD fs G[p.G197fs]ASPRSPSPGSGARSLSVE SLSVEM,KVRPTSCRT,SPGSGARSL,RPTSCRTAP,VMHPRG MCTPCEKPGRPSNEESWWKVRPTSCR ASP,SSGEQQMGF,GEQQMGFFI,EQQMGFFIL,RPSNEES TAPSLTCVGPLSSGEQQMGFFILQLRST WW,QQMGFFILQL,VMHPRGASPR,SVEMCTPCEK,QMGF * FILQLR,RSPSPGSGAR,KVRPTSCRTA,WWKVRPTSCR,HPR GASPRSP,RPTSCRTAPS,APSLTCVGPL,GPLSSGEQQM,SG ARSLSVEM,LSSGEQQMGF,GEQQMGFFIL,EESWWKVRPT PEX1 c.1108de|A p.I370f QSKTKQNVLSPEKEKQMSEPLDQKK[p. KLGQIIMKK,KMRRPVCYK,IMKKMRRPV,QIIMKKMRR,M BLCA,PRAD s I370fs]LGQIIMKKMRRPVCYK* KKMRRPVC,QKKLGQIIM,KKMRRPVCY,IIMKKMRRPV,KK MRRPVCYK,IMKKMRRPVC,DQKKLGQIIM,KLGQIIMKKM, MKKMRRPVCY PFKM c.352C>A p.R118 TSGGDAQGMNAAVRAVVRVGIFTGA[p. FTGASVFFV,SVFFVHEGY,IFTGASVFF,GIFTGASVF,VGIFT LUAD S R118S]SVFFVHEGYQGLVDGGDHIK GASV,RVGIFTGASV,ASVFFVHEGY,IFTGASVFFV,VGIFTGA EATWES SVF,GIFTGASVFF PFKP c.1779de|G p.M59 SGTKRRVFIIETMGGYCGYLANMGG[p. ELMPHTFSK,GSRPELMPH,HTFSKSPST,YLANMGGSR,STS STAD 3fs M593fs]SRPELMPHTFSKSPSTSGICSP GICSPT,RPELMPHTF,NMGGSRPEL,SKSPSTSGI,TSGICSPT TWST* W,MPHTFSKSPS,ANMGGSRPEL,NMGGSRPELM,SRPEL MPHTF,FSKSPSTSGI,STSGICSPTW PGAM c.719G>A p.R240 PIVYELDKNLKPIKPMQFLGDEETV[p.R TVHKAMEAV,ETVHKAMEA,HKAMEAVAA,DEETVHKAM, CRC 1 H 240H]HKAMEAVAAQGKAKK* ETVHKAMEAV,EETVHKAMEA PGAP c.1694T>G p.F565 QAPSSTEISLKLHIAQPENNTHVAL[p.F5 THVALCKMY,NTHVALCKMY OV 1 C 65C]CKMYTSSDCRYEVTVKTSFSQILG QV PGM5 c.1277_127 p.G426 VWLSIIAARKQSVEEIVRDHWAKFG[p. HWAKFGPPL,AKFGPPLLL,HWAKFGPPLL,KFGPPLLLQV KIRC 8insC fs G426fs]PPLLLQV* PGM5 c.292A>G p.I98V RTAIEIVVQMAAANGIGRLIIGQNG[p.I RLIIGQNGV,VLSTPAVSCI,RLIIGQNGVL,GQNGVLSTPA STAD 98V]VLSTPAVSCIIRKIKAAGGIILTASH PGPEP c.490_491i p.R164f KGCAALIHVPPLSRGLPASLLGRAL[p.R1 SQRELTGGL,ASLLGRALK,RALKSHHPG,KSHHPGNAG,KAQ KIRC 1L nsA s 64fs]KSHHPGNAGRGGKAQAQSPVRR AQSPVR,QAQSPVRRK,GKAQAQSPV,AQSPVRRKL,RKLNH KLNHGPSSQRELTGGLLL* GPSS,RELTGGLLL,ALKSHHPGNA,KLNHGPSSQR,KSHHPG NAGR,KAQAQSPVRR,AQAQSPVRRK,SQRELTGGLL PHAC c.752_753i p.V251 LPCLPVKLSPPLPPKKVMICMPVGG[p.V ALPDPAPAA,AVRQPRPAP,RQPRPAPPL,MICMPVGGA,M LAML TR1 nsG fs 251fs]ARPLTGVLHSPEEWPAGCGPAP PVGGARPL,GARPLTGVL,GPAPPHCPA,LPDPAPAAV,LPPH PHCPALPDPAPAAVRQPRPAPPLHHRL APLGL,HRLPPHAPL,AQQNAGHDH,WPAGCGPAP,VMIC PPHAPLGLQNDRRAQQNAGHDHAEA MPVGGA,VLHSPEEWPA,ALPDPAPAAV,RLPPHAPLGL,C GKL* MPVGGARPL,MICMPVGGAR,GARPLTGVLH,AVRQPRPA PP,AGHDHAEAGK,MPVGGARPLT,GPAPPHCPAL,CPALPD PAPA,RPAPPLHHRL,HHRLPPHAPL,EEWPAGCGPA,VRQP RPAPPL,RQPRPAPPLH,AQQNAGHDHA,WPAGCGPAPP PHAC c.753de|G p.V251 LPCLPVKLSPPLPPKKVMICMPVGG[p.V RVWPSTTTL,TTTLSCPPR,RVASRVWPS,ASRVWPSTT,RSS STAD TR1 fs 251fs]QTSHWCPTQPRRVASRVWPST TSCSTA,HWCPTQPRR,TQPRRVASR,CPTQPRRVA,QPRRV TTLSCPPRSSTSCSTAATASTSPPPPAPS ASRV,WPSTTTLSC,GQTSHWCPT,SRVWPSTTT,MPVGGQ PCTPRAAE* TSH,TSHWCPTQPR,STTTLSCPPR,RVASRVWPST,ASRVW PSTTT,RSSTSCSTAA,STSCSTAATA,PTQPRRVASR,CPTQP RRVAS,QPRRVASRVW,APSPCTPRAA,MPVGGQTSHW,SR VWPSTTTL PHAC c.711_712i p.S237f APVPPPKPASRNTTREAAGSSHSKK[p.S SSHSKKNNWL STAD TR2 nsA s 237fs]NNWL* PHAC c.1061de|C p.S354f DEREKSTCSMGSELLPMISPRSPSP[p.S CLLIYLQSL,YLQSLHAPL,SLHAPLHSL,RLFKLCQKL,LIYLQSL STAD TR4 s 354fs]HCLLIYLQSLHAPLHSLLRLFKLCQ HA,RSPSPHCLL,LHSLLRLFK,HAPLHSLLR,SPSPHCLLI,SPHC KLSFHHP* LLIYL,APLHSLLRL,LQSLHAPLH,LHAPLHSLL,FKLCQKLSF,LL IYLQSLHA,SLHAPLHSLL,PLHSLLRLFK,LLRLFKLCQK,RSPSP HCLLI,IYLQSLHAPL,LFKLCQKLSF,SPSPHCLUY,SPRSPSPH CL,APLHSLLRLF,YLQSLHAPLH,QSLHAPLHSL PHC3 c.104_106d p.T35d STAMDTEPNPGTSSVSTTTSSTTTT[p.T TTSSTTTTI,TTTSSTTTTI GBM e|CCA e| 35de|]ITTSSSRMQQPQISVYSGSDRHA VQVIQ PHGD c.517_518 p.G173 LGILGLGRIGREVATRMQSFGMKTI[p.G KTILYDPII,SFGMKTILY,QSFGMKTIL,MKTILYDPI,GMKTILY SKCM H GG>TT L 173L]LYDPIISPEVSASFGVQQLPLEEIW DPI,QSFGMKTILY,LYDPIISPEV,MQSFGMKTIL,MKTILYDPI PL I PHIP c.5043C>G p.I1681 KKRGRKPKKLQYAKPEDLEQNNVHP[p. EQNNVHPMR,NVHPMRDEV,LEQNNVHPM,HPMRDEVL LUSC M I1681M]MRDEVLPSSTCNFLSETNNVK PS EDLLQ PHOS c.95_97de| p.S32de| PWPANQPLPGGLLPRPLSLAPSSSS[p.S SLAPSSSSC,SLAPSSSSCC PRAD PHO1 CCT 32de|]CCSPPCSQDGRMAAQGAPRFLL TFDFDE PI15 c.64G>T p.V22F MIAISAVSSALLFSLLCEAST[p.V22F]FV LLCEASTFV,SLLCEASTF,CEASTFVLL,SLLCEASTFV,LLCEAS LUAD LLNSTDSSPPTNNFTDIEAALKAQ TFVL,FSLLCEASTF PIAS2 c.1556C>T p.S519 SETQSSPTKGVLMYQPSSVRVPSVT[p.S SVRVPSVTL,SVRVPSVTLV,SSVRVPSVTL CRC L 519L]LVDPAAIPPSLTDYSVPFHHTPISS M PIAS3 c.1378G>A p.D460 GGDPSENKKKVEVIDLTIESSSDEE[p.D4 IESSSDEENL CESC N 60N]NLPPTKKHCSVTSAAIPALPGSKG VL PIAS3 c.348de|C p.H116 LAPIPPTLLAPGTLLGPKREVDMHP[p.H KREVDMHPL,REVDMHPLC,DMHPLCPSL,HPLCPSLCTL,V STAD fs 116fs]LCPSLCTLMSP* DMHPLCPSL,REVDMHPLCP PIGM c.674G>T p.R225 NDKSLRQFRYTFQACLYELLKRLCN[p.R RLCNLAVLL,NLAVLLFVA,LLKRLCNLA,LAVLLFVAV,ELLKRL LUAD L 225L]LAVLLFVAVAGLTFFALSFGFYYEY CNL,LKRLCNLAV,KRLCNLAVL,LCNLAVLLF,NLAVLLFVAV,L G LKRLCNLAV,RLCNLAVLLF,YELLKRLCNL,LKRLCNLAVL,KRL CNLAVLL PIGO c.2361de|C p.P787fs VTVLVKAGAGAPRTRTVLTPFSGPP[p.P KLTWIMWSL,WIMWSLKST,LTWIMWSLK,SLKSTDTCR,TP STAD 787fs]LLKLTWIMWSLKSTDTCRRSSGA FSGPPLL,LLKLTWIMW,VLTPFSGPPL,KLTWIMWSL,SLKS G* TDTCRR,LKLTWIMWSL PIGR c.548T>G p.V183 NAQKRKSLYKQIGLYPVLVIDSSGY[p.V SSGYGNPNY,DSSGYGNPNY TGCT G 183G]GNPNYTGRIRLDIQGTGQLLFSV VIN PIGT c.1037de|C p.A346fs TAMINNSRNLNIQLKWKRPPENEAP[p. NEAPQCPSCM STAD A346fs]QCPSCMPSGT* PIK3C c.4419C>G p.F147 EELNGYIWHLIHAPPEVAECDLVYT[p.F LVYTLFHPL,YTLFFIPLPR,AECDLVYTL,DLVYTLFFIPL,LFHPL KIRC 2B 3L 1473L]LFHPLPRDEKAMGTSPAPKSSD PRDEK,VYTLFHPLPR,AECDLVYTLF GTWA PIK3C c.859de|C p.R287fs PLDFSKDTSGKPVARSKTMPPQVPP[p. TMPPQVPPA,LLHFATCWI,AMSGVLSPL,RLARTAGFL,FLQ GBM 2B R287fs]APMPPAMATERMRRLARTAG PRWAPG,LLPMAMSCL,EMRRLLHFA,WISFDLALT,VLSPLA FLQPRWAPGPTLLPMAMSCLRSQKRE QST,AMATERMRR,AMSCLRSQK,RTAGFLQPR,RWAPGPT MRRLLHFATCWISFDLALTSKTTSSLAM LL,REMRRLLHF,HFATCWISF,CWISFDLAL,RMRRLARTA,R SGVLSPLAQSTSGMRST* SQKREMRR,TSKTTSSLA,LPMAMSCLR,MSCLRSQKR,LTSK TTSSL,TSSLAMSGV,PPQVPPAPM,VPPAPMPPA,PPAPMP PAM,APMPPAMAT,QPRWAPGPT,APGPTLLPM,GPTLLP MAM,MATERMRRL,CLRSQKREM,RRLARTAGF,PRWAPG PTL,SQKREMRRL,QKREMRRLL,RLLHFATCW,SKTTSSLAM, SSLQMSGVL,LAMSGVISP,TLLPMAMSCL,RLLHFATCWI,L AMSGVLSPL,AMSGVLSPLA,KTMPPQVPPA,AMATERMR RL,ALTSKTTSSL,TTSSLAMSGV,MAMSCLRSQK,ISFDLALTS K,ATERMRRLAR,RMRRLARTAG,CLRSQKREMR,RSQKRE MRRL,SQKREMRRLL,TSKTTSSLAM,RTAGFLQPRW,LLPM AMSCLR,AMSCLRSQKR,QVPPAPMPPA,FATCWISFDL,LT SKTTSSLA,MPPQVPPAPM,VPPAPMPPAM,MPPAMATER M,QPRWAPGPTL,SPLAQSTSGM,MRRLARTAGF,EMRRLL HFAT,RRLARTAGFL,WAPGPTLLPM,KREMRRLLFIF,REMR RLLHFA,RRLLHFATCW,LHFATCWISF,AQSTSGMRST,LPM AMSCLRS PIK3C c.1035T>A p.N345 GETSTKSLWVINSALRIKILCATYV[p.N3 ILCATYVKV,KILCATYVK,KVNIRDIDK,ATYVKVNIR,KILCATY BRCA,CRC, A K 45K]KVNIRDIDKIYVRTGIYHGGEPLCD VKV,TYVKVNIRDI,CATYVKVNIR STAD,UCEC N PIK3C c.1049A>G p.D350 KSLWVINSALRIKILCATYVNVNIR[p.D3 YVNVNIRGI,NVNIRGIDK,NIRGIDKIY,TYVNVNIRGI,VNIRG CRC A G 50G]GIDKIYVRTGIYHGGEPLCDNVNT IDKIY QR PIK3C c.113G>A p.R38H IHLMPPRILVECLLPNGMIVTLECL[p.R3 VTLECLHEA,LECLHEATL,CLHEATLITI,HEATLITIKH,LECLH UCEC A 8H]HEATLITIKHELFKEARKYPLHQLLQ EATLI PIK3C c.115G>A p.E39K HLMPPRILVECLLPNGMIVTLECLR[p.E IVTLECLRK,LRKATLITI,LECLRKATL,CLRKATLITI,MIVTLECL UCEC A 39K]KATLITIKHELFKEARKYPLHQLLQD RK,RKATLITIKH,LECLRKATLI PIK3C c.1258T>C p.C420 DLPRAARLCLSICSVKGRKGAKEEH[p.C KEEHRPLAW,GAKEEHRPLA,RPLAWGNINL,AKEEHRPLA BRCA,UCEC A R 420R]RPLAWGNINLFDYTDTLVSGKM W ALNL PIK3C c.1338_136 p.PVPH LAWGNINLFDYTDTLVSGKMALNLW[p. ALNLWLNPI,NLWLNPIGV,GKMALNLWL,MALNLWLNPI BRCA A 4de|GCCAG GLEDL4 PVPHGLEDL447de|]LNPIGVTGSNPN TACCTCAT 47de| KETPCLELEFDWFSSVVKFPDMSVIEEH GGATTAGA ANWSVSREAGFS AGATTT PIK3C c.1357G>A p.E453 NLFDYTDTLVSGKMALNLWPVPHGL[p. GLKDLLNPI,LWPVPHGLK,VPHGLKDLL,NLWPVPHGLK,W BRCA A K E453K]KDLLNPIGVTGSNPNKETPCLEL PVPHGLKDL,HGLKDLLNPI EFD PIK3C c.1364_136 p.L455fs DYTDTLVSGKMALNLWPVPHGLEDL[p. GLEDLAEPY,DLAEPYWCY,AEPYWCYWI,LAEPYWCYW,H BRCA A 5insG L455fs]AEPYWCYWIKSK* GLEDLAEPY PIK3C c.1624G>A p.E542 LARDNELRENDKEQLKAISTRDPLS[p.E ISTRDPLSK,STRDPLSKI,LSKITEQEK,AISTRDPLSK,SKITEQE BLCA,BRCA, A K 542K]KITEQEKDFLWSHRHYCVTIPEILP KDF CESC, K CRC,HNSC, LUAD,LUSC, STAD,UCEC PIK3C c.1633G>A p.E545 DNELRENDKEQLKAISTRDPLSEIT[p.E5 SEITKQEKDF,KQEKDFLWSH BLCA,BRCA, A K 45K]KQEKDFLWSHRHYCVTIPEILPKLL CESC,CRC,GBM, L HNSC,KIRC, LUAD,LUSC, STAD,TGCT, UCEC,UCS PIK3C c.1634A>C p.E545 DNELRENDKEQLKAISTRDPLSEIT[p.E5 TAQEKDFLW,SEITAQEKDF,AQEKDFLWSH,ITAQEKDFLW BRCA,CRC A A 45A]AQEKDFLWSHRHYCVTIPEILPKLL L PIK3C c.1634A>G p.E545 DNELRENDKEQLKAISTRDPLSEIT[p.E5 SEITGQEKDF,GQEKDFLWSH CRC A G 45G]GQEKDFLWSHRHYCVTIPEILPKLL L PIK3C c.1636C>A p.Q546 NELRENDKEQLKAISTRDPLSEITE[p.Q5 KEKDFLWSH,TEKEKDFLW,SEITEKEKDF BRCA,CRC,UCEC A K 46K]KEKDFLWSHRHYCVTIPEILPKLLLS PIK3C c.1637A>C p.Q546 NELRENDKEQLKAISTRDPLSEITE[p.Q5 EITEPEKDFL,SEITEPEKDF,EPEKDFLWSH UCEC A P 46P]PEKDFLWSHRHYCVTIPEILPKLLLS PIK3C c.1637A>G p.Q546 NELRENDKEQLKAISTRDPLSEITE[p.Q5 REKDFLWSH,TEREKDFLW,SEITEREKDF BRCA,UCEC A R 46R]REKDFLWSHRHYCVTIPEILPKLLLS PIK3C c.1A>G p.M1V [p.M1V]VPPRPSSGELWGIHLMPPRILV VPPRPSSGEL GBM A ECLL PIK3C c.2176G>A p.E726 HLNRQVEAMEKLINLTDILKQEKKD[p.E7 KTQKVQMKF,KDKTQKVQMK,KTQKVQMKFL,KKDKTQKV BRCA,CESC, A K 26K]KTQKVQMKFLVEQMRRPDFMD QM LUSC ALQGF PIK3C c.263G>A p.R88Q QDESSYIFVSVTQEAEREEFFDETR[p.R8 RQLCDLRLF,ETRQLCDLR,EEFFDETRQL BRCA,CRC,GBM, A 8Q]QLCDLRLFQPFLKVIEPVGNREEKIL STAD,UCEC PIK3C c.278G>A p.R93Q YIFVSVTQEAEREEFFDETRRLCDL[p.R9 QLFQPFLKV,LQLFQPFLK,RRLCDLQLF,CDLQLFQPF,LQLF UCEC A 3Q]QLFQPFLKVIEPVGNREEKILNREIG QPFLKV,QLFQPFLKVI,DLQLFQPFLK,TRRLCDLQLF,LCDLQ LFQPF,CDLQLFQPFL PIK3C c.3012G>A p.M10 RFQEMCYKAYLAIRQHANLFINLFS[p. NLFINLFSI,FINLFSIML,LFINLFSIM,FSIMLGSGM,IMLGSG BRCA A 04I M1004I]IMLGSGMPELQSFDDIAYIRKT MPEL,NLFINLFSIM,LFINLFSIML,LFSIMLGSGM LALD PIK3C c.3127A>G p.M10 DIAYIRKTLALDKTEQEALEYFMKQ[p.M104 ALEYFMKQV,FMKQVNDAH,MKQVNDAHH,EALEYFMKQ GBM,HNSC,UCEC A 43V 3V]VNDAHHGGWTTKMDWIFHTI V,FMKQVNDAHH KQHALN PIK3C c.3129G>A p.M10 DIAYIRKTLALDKTEQEALEYFMKQ[p.M1 FMKQINDAH,KQINDAHHG,EALEYFMKQI,FMKQINDAHH, BRCA,UCEC A 43I 043I]INDAHHGGWTTKMDWIFHTIK KQINDAHHGG QHALN PIK3C c.3130A>T p.N104 IAYIRKTLALDKTEQEALEYFMKQM[p.N MYDAHHGGW,FMKQMYDAH,LEYFMKQMY,MKQMYDA BRCA A 4Y 1044Y]YDAHHGGWTTKMDWIFHTIK HH,KQMYDAHHG,ALEYFMKQMY,FMKQMYDAHH,QMY QHALN* DAHHGGW,KQMYDAHHGG PIK3C c.3132T>A p.N104 IAYIRKTLALDKTEQEALEYFMKQM[p.N FMKQMKDAH,KQMKDAHHG,MKDAHHGGW,ALEYFMK KIRC A 4K 1044K]KDAHHGGWTTKMDWIFHTIK QMK,FMKQMKDAHH,KQMKDAHHGG,QMKDAHHGGW QHALN* PIK3C c.3140A>G p.H104 IRKTLALDKTEQEALEYFMKQMNDA[p. FMKQMNDAR,KQMNDARHG,RHGGWTTKM,YFMKQM BRCA,CRC, A 7R H1047R]RHGGWTTKMDWIFHTIKQH NDAR,FMKQMNDARH,KQMNDARHGG,QMNDARHGG GBM,HNSC, ALN* W,ARHGGWTTKM LIHC, LUSC,STAD, UCEC,UCS PIK3C c.3140A>T p.H104 IRKTLALDKTEQEALEYFMKQMNDA[p. FMKQMNDAL,ALHGGWTTK,KQMNDALHG,LHGGWTTK BRCA,HNSC, A 7L H1047L]LHGGWTTKMDWIFHTIKQHA M,QLHGGWTTKM,YFMKQMNDAL,DALHGGWTTK,FMK UCEC LN* QMNDALH,KQMNDALHGG,QMNDALHGGW PIK3C c.317G>T p.G106 EFFDETRRLCDLRLFQPFLKVIEPV[p.G1 FLKVIEPVV,KVIEPVVNR UCS A V 06V]VNREEKILNREIGFAIGMPVCEFD MV PIK3C c.323G>A p.R108 FDETRRLCDLRLFQPFLKVIEPVGN[p.R1 HEEKILNREI UCEC A H 08H]HEEKILNREIGFAIGMPVCEFDMV KD PIK3C c.325_327d p.E110 ETRRLCDLRLFQPFLKVIEPVGNRE[p.E1 REKILNREI BRCA,UCEC A e|GAA de| 10de|]KILNREIGFAIGMPVCEFDMVKD PEVQD PIK3C c.331A>G p.K111 TRRLCDLRLFQPFLKVIEPVGNREE[p.K1 REEEILNREI,EEILNREIGF UCEC A E 11E]EILNREIGFAIGMPVCEFDMVKDP EV PIK3C c.331_333d p.K111 TRRLCDLRLFQPFLKVIEPVGNREE[p.K1 REEILNREI,EEILNREIGF BRCA A e|AAG de| 11de|]ILNREIGFAIGMPVCEFDMVKDP EVQDF PIK3C c.1141T>C p.C381 CFALYAVIEKAKKARSTKKKSKKAD[p.C3 KSKKADRPI,RPIAWANLM,KKADRPIAW,KSKKADRPIA,RPI TGCT D R 81R]RPIAWANLMLFDYKDQLKTGERC AWANLML,KKSKKADRPI,SKKADRPIAW,ADRPIAWANL LYM PIK3C c.493G>A p.V165I RHPPSEESQAFQRQLTALIGYDVTD[p.V LIGYDVTDI,ALIGYDVTDI LUAD G 165I]ISNVHDDELEFTRRGLVTPRMAEV AS PIK3R c.1126G>A p.G376 ADGTFLVRDASTKMHGDYTLTLRKG[p. TLRKGRNNK,KGRNNKLIK,YTLTLRKGR,RNNKLIKIF,LTLRK GBM 1 R G376R]RNNKLIKIFHRDGKYGFSDPLTF GRNNK,TLRKGRNNKL,KGRNNKLIKI,GRNNKLIKIF SSV PIK3R c.1137A>T p.K379 TFLVRDASTKMHGDYTLTLRKGGNN[p. KGGNNNLIK,NNLIKIFHR,RKGGNNNLI,GNNNLIKIF,TLRKG GBM 1 N K379N]NLIKIFHRDGKYGFSDPLTFSSV GNNNL,NNNLIKIFHR,GGNNNLIKIF VEL PIK3R c.1697_170 p.KPDL RRRLEEDLKKQAAEYREIDKRMNSI[p.K RMNSIIQLR,MNSIIQLRK,SIIQLRKTR,KRMNSIIQL,RMNSII BRCA 1 8de|TTAAA 567de| PDL567de|]IQLRKTRDQYLMWLTQKG QLRK,NSIIQLRKTR CCAGACC VRQKKLNEWLGNENTEDQY PIK3R c.1112T>G p.L371 LLSTSSLASHDSTLSLASSQASGPA[p.L3 SSQASGPAR,RSRHLLTSF,GPARSRHLL,ASSQASGPAR,RSR KIRC 5 R 71R]RSRHLLTSFVSGLSDGMDSGYVED HLLTSFV,ARSRHLLTSF SE PILRA c.872_873i p.S291f VYASLALSSSTSPRAPPSHRPLKSP[p.S2 SPPERDPVL LUAD nsC s 91fs]PERDPVLCLKGLTNGQPSQD* PIM1 c.490C>T p.L164 LQEELARSFFWQVLEAVRHCHNCGV[p. RHCHNCGVF,HCHNCGVFHR,VRHCHNCGVF DLBCL F L164F]FHRDIKDENILIDLNRGELKLIDF GS PIM1 c.550C>T p.L184 HNCGVLHRDIKDENILIDLNRGELK[p.L1 FIDFGSGAL,RGELKFIDF,FIDFGSGALL,IDLNRGELKF,LKFID DLBCL F 84F]FIDFGSGALLKDTVYTDFDGTRVYS FGSGA,KFIDFGSGAL,GELKFIDFGS P PIP4K c.656G>A p.R219 IVTRNVFSHRLSVYRKYDLKGSTVA[p.R TVAKEASDK,KEASDKEKA,STVAKEASDK,VAKEASDKEK KIRP 2A K 219K]KEASDKEKAKELPTLKDNDFINEG QK PIP4K c.611G>A p.R204 NTLLPQFLGMYRVSVDNEDSYMLVM[p. VMHNMFSHR,LVMHNMFSH,SYMLVMHNM,YMLVMHN CRC 2C H R204H]HNMFSHRLPVHRKYDLKGSL MF,MHNMFSHRL,VMHNMFSHRL,LVMHNMFSHR,SYML VSREAS VMHNMF,DSYMLVMHNM,HNMFSHRLPV,MLVMHNMF SH PITPN c.884de|C p.P295fs PPGKPSTEARSAASNTGTPDGPEAP[p. AQMPPPMPA,QMPPPMPAL,CLSGACRTL,TLPETLRTA,RT STAD M1 P295fs]QAQMPPPMPALGSSGPHPPV VRRSSPR,ETLRTAPRK,RTAPRKSSL,RKSSLMPTK,KSSLMPT PPTHPNMEGLCLPRACLSGACRTLPETL KA,SLMPTKASR,ASRTVRRSS,TVRRSSPRR,NMEGLCLPR,G RTAPRKSSLMPTKASRTVRRSSPRR* PEAPQAQM,HPNMEGLCL,LPRACLSGA,MPTKASRTV,PQ AQMPPPM,MEGLCLPRA,AQMPPPMPAL,CLPRACLSGA,S LMPTKASRT,LMPTKASRTV,RTVRRSSPRR,SSLMPTKASR, RTLPETLRTA,RTAPRKSSLM,PTKASRTVRR,APQAQMPPP M,MPALGSSGPH,LPRACLSGAC,APRKSSLMPT,LRTAPRKS SL,RKSSLMPTKA PIWIL c.2095G>A p.V699 GLKVCLQAALRAWNSCNEYMPSRII[p. RIIMYRDGV,EYMPSRIIM,YMPSRIIMY,MPSRIIMYR,YMPS HNSC 1 M V699M]MYRDGVGDGQLKTLVNYEVP RIIMYR,NEYMPSRIIM QFLDCL PKD1 c.2813C>T p.T938 VENSASRANLSLRVTAEEPICGLRA[p.T AMPSPEARV,RAMPSPEAR,EPICGLRAM,MPSPEARVL,GL TGCT M 938M]MPSPEARVLQGVLVRYSPVVEA RAMPSPEA,RAMPSPEARV,AMPSPEARVL,EEPICGLRAM GSDM PKD2 c.1457A>T p.Y486 KLIRYVTTFDFFLAACEIIFCFFIF[p.Y486 FCFFIFFYV,IIFCFFIFF,CFFIFFYVV,IFFYVVEEI,FFYVVEEIL,IF CLL F F]FYVVEEILEIRIHKLHYFRSFWNCLD CFFIFFY,FCFFIFFYVV,FIFFYVVEEI,IIFCFFIFFY,IFCFFIFFYV, IFFYVVEEIL,FYVVEEILEI,EIIFCFFIFF PKHD c.5568C>A p.F185 PPVASLSPTSGSIGGGTTLVITGNG[p.F1 LVITGNGLY,GLYPGNTTV,TLVITGNGL,GLYPGNTTVT,LYP CRC 1L1 6L 856L]LYPGNTTVTIGDEPCQIISINPNEV GNTTVTI,TLVITGNGLY,TTLVITGNGL Y PKN2 c.226de|A p.K76fs KREIRKELKIKEGAENLRKVTTDKK[p.K7 TTDKKVWLM,RKVTTDKKVW STAD 6fs]VWLM* PLA2G c.689de|G p.W23 FLQRQPQAWKDKYIRAFVSLGAPWG[p. WLQETTTGS,AWPRPCASW,GAPWGAWPR,WPRPCASW STAD 15 0fs W230fs]AWPRPCASWLQETTTGSQSS L,SLGAPWGAW,FVSLGAPWGA,LGAPWGAWPR,VSLGAP GP* WGAW,GAWPRPCASW PLA2G c.157_158i p.L53fs KMIKCVIPGSDPFLEYNNYGCYCGL[p.L ALARQSPVA,SVRPSFATA,TLPSAFQKL,PLSASSHTV,ATLPS STAD 1B nsTG 53fs]WGAOAPPWMNWTSAARHMTT AFQK,SSHTVLSNK,MTTAMTRPR,AVNFCWTTR,NYGCYC AMTRPRSWTAVNFCWTTRTPTPIHTR GLW,LWGAQAPPW,SWTAVNFCW,SFATATATL,AARHM ALARQSPVAAKTKSVRPSFATATATLPS TTAM,RHMTTAMTR,MTRPRSWTA,RSWTAVNFC,TTRTP AFQKLHITRHTRTWTPRSIVRVEYHLSK TPIH,RTPTPIHTR,HTRALARQS,RALARQSPV,LARQSPVAA, ASPLSASSHTVLSNKAPC* KTKSVRPSF,KLHITRHTR,ITRHTRTWT,HTRTWTPRS,RTW TPRSIV,RSIVRVEYH,RVEYHLSKA,LSKASPLSA,WMNWTSA AR,AFQKLHITR,TWTPRSIVR,WTSAARHMT,WTAVNFCW T,WTTRTPTPI,WTPRSIVRV,RPRSWTAVN,TPIHTRALA,RP SFATATA,YHLSKASPL,ATATLPSAF,AQAPPWMNW,TAMT RPRSW,RQSPVAAKT,FQKLHITRH,HITRHTRTW,SKASPLS AS,LSASSHTVL,VEYHLSKAS,AMTRPRSWTA,MTRPRSWT AV,ALARQSPVAA,ATATATLPSA,HLSKASPLSA,RTWTPRSI VR,IVRVEYFILSK,ASSFITVLSNK,TAVNFCWTTR,TATLPSAF QK,SAFQKLHITR,RSWTAVNFCW,CWTTRTPTPI,AARHMT TAMT,TTRTPTPIHT,RTPTPIHTRA,HTRALARQSP,RALARQ SPVA,LARQSPVAAK,RQSPVAAKTK,KTKSVRPSFA,KSVRPS FATA,SVRPSFATAT,KLHITRHTRT,ITRHTRTWTP,HTRTWT PRSI,RSIVRVEYHL,SSHTVLSNKA,PWMNWTSAAR,HMTT AMTRPR,TPIHTRALAR,TSAARHMTTA,WTAVNFCWTT,A PPWMNWTSA,SAARHMTTAM,RPRSWTAVNF,TPTPIHTR AL,SPVAAKTKSV,RPSFATATAT,LPSAFQKLHI,SPLSASSHT V,MNWTSAARHM,TATATLPSAF,GLWGAQAPPW,WMN WTSAARH,AKTKSVRPSF,PSFATATATL,FQKLHITRHT,LHIT RHTRTW,KASPLSASSH,TPRSIVRVEY PLA2G c.602G>A p.R201 GPDLCCREHDRCPQNISPLQYNYGI[p.R IQNYRFHTI,NYGIQNYRF,QYNYGIQNY,YNYGIQNYR,LQY UCEC 3 Q 201Q]QNYRFFITISFICDCDTRFQQCLQ NYGIQN,YNYGIQNYRF,LQYNYGIQNY,QYNYGIQNYR,IQN NQHD YRFHTIS,QNYRFHTISH PLAG1 c.551de|A p.K184fs FESTGVLLEHLKSHAGKSSGGVKEK[p.K RMSGDTWWC,TLEERTSSV,VIAGSTPER,RTSSVSIVH,TSSV STAD 184fs]STSANIVIAGSTPERMSGDTWW SIVHR,GVKEKSTSA,KSTSANIVI,TWWCTLEER,IVHRDLGE CTLEERTSSVSIVHRDLGERIT* R,STSANIVIA,KEKSTSANI,EERTSSVSI,RMSGDTWWCT,CT LEERTSSV,IVIAGSTPER,RTSSVSIVHR,KSTSANIVIA,DTW WCTLEER,SIVHRDLGER,KEKSTSANIV,MSGDTWWCTL,LE ERTSSVSI,EERTSSVSIV,TPERMSGDTW PLAGL c.30de|C p.P10fs MTTFFTSVPP[p.P10fs]GFKMQSRRRK FTSVPPGFK,FFTSVPPGF,TSVPPGFKM,KMQSRRRKW,FFT STAD 2 WAGN* SVPPGFK,TFFTSVPPGF,GFKMQSRRRK,KMQSRRRKWA,F TSVPPGFKM,FKMQSRRRKW PLAU c.602_603i p.R201fs IIGGEFTTIENQPWFAAIYRRHRGG[p.R LLGDQRHTL,VWRQPHQPL,HLRVWRQPH,GLCHLRVWR, STAD nsG 201fs]LCFILRVWRQPHQPLLGDQRHTL RHRGGLCHL,WRQPHQPLL,LLGDQRHTLL,VWRPHQPLL, LH* AIYRRHRGGL,RHRGGLCHLR,HLRVWRQPHQ,RVWRQPH QPL,RRHRGGLCHL,RGGLCHLRVVV PLCD3 c.1495de|G p.E499f KGRVLVKGKKLPAARSEDGRALSDR[p. WLCTATPPA,RALSDRRRR,RRRRRRMTR,RRRRRMTRR,RR CLL s E499fs]RRRRRMTRRKKRRWRLQRRG RRMTRRK,RRRMTRRKK,RMTRRKKRR,KKRRWRLQR,KRR GWPSRSPRSCRPWLCTATPPA* WRLQRR,RWRLQRRGG,GGWPSRSPR,WPSRSPRSC,SPRS CRPWL,RRKKRRWRL,LQRRGGWPS,RSPRSCRPW,RALSD RRRRR,ALSDRRRRRR,RRRRRRMTRR,RRRRRMTRRK,RRR RMTRRKK,MTRRKKRRWR,RKKRRWRLQR,KKRRWRLQRR, RWRLQRRGGW,LQRRGGWPSR,RGGWPSRSPR,RSPRSC RPWL,RSCRPWLCTA,RPWLCTATPP,TRRKKRRWRL,RMT RRKKRRW,SRSPRSCRPW PLCE1 c.1315G>T p.G439 NTVGSLLHFLTKLPASETAHGRISV[p.G RISVCPCLK,GRISVCPCL,HGRISVCPCL LUSC C 439C]CPCLKQCVRDTVCEYRATLQRTSI SQ PLCE1 c.1690G>T p.G564 LMEQEQTIYRRVLPVDYLCFLTRDL[p.G CTPECQSSL LUAD C 564C]CTPECQSSLPCLKASISASILTTQN G PLCL1 c.1692G>T p.M56 VKGKKLPSDPDVLEGEVTDEDEEAE[p. ISRRMSVDY,AEISRRMSV,EEAEISRRM,EISRRMSVDY,DEE LUAD 4I M564I]ISRRMSVDYNGEQKQIRLCREL AEISRRM SDLV PLEC c.4157G>A p.R138 QDARRRQEQIQAMPLADSQAVREQL[p. EQLQQEQAL,REQLQQEQA,REQLQQEQAL,EQLQQEQALL, ACC 6Q R1386Q]QQEQALLEEIERHGEKVEEC QQEQALLEEI QRFAKQ PLEKH c.329G>T p.R110 VDRCLFYYKDEKEESILGSIPLLSF[p.R11 SIPLLSFLV,LLSFLVAAV,FLVAAVQPS,IPLLSFLVA,GSIPLLSF LUAD A6 L 0L]LVAAVQPSDNISRKHTFKAEHAGVR L,GSIPLLSFLV,PLLSFLVAAV,IPLLSFLVAA T PLEKH c.982de|G p.V328fs TNPDKIAQRKSSMNQLQQWVNLRRG[p. RLKTFGVPL,CLAGSLSTM,SAMPSAMGV,IMMSWMPPL, CRC,STAD A6 V328fs]YPRLKTFGVPLGSILCLAGSLS MMSWMPPLA,WMPPLAPCA,FTPLSAHPV,PLSAHPVPV, TMAPTPPSTPMIISTTRQECGRRASVPC VLSGCHLAV,NLRRGYPRL,TMAPTPPST,AMPSAMGVA,R RPMIGSARPGPWRTSAMPSAMGVAL MPPSGSQA,HLAVRTSML,RGYPRLKTF,RAPTAVPAF,LR PTSCESGRSPPATGGRMPPSGSQAPPG RGYPRLK,STMAPTPPS,RASVPCRPM,SARPGPWRT,RTSAMP SQSIMMSWMPPLAPCAACPCSPAPTL SAM,AVRTSMLTL,QWVNLRRGY,VNLRRGYPR,TPMIISTT CPAHPARAPTAVPAFTPLSAHPVPVLSG R,STTRQECGR,TLCPAHPAR,CAACPCSPA,TAVPAFTPL,YP CHLAVRTSMLTLLPM* RLKTFGV,APTPPSTPM,RPGPWRTSA,MPSAMGVAL,SPPA TGGRM,APPGSQSIM,MPPLAPCAA,CPCSPAPTL,SPAPTLC PA,HPARAPTAV,VPAFTPLSA,VPVLSGCHL,SQSIMMSWM,TS MLTLLPM,FGVPLGSIL,RQECGRRAS,IGSARPGPW,WRTSQMPSA, SAMGVALPT,CESGRSPPA,SQAPPGSQS,GSQSIMMSW,MSWMPPLAP, ARAPTAVPA,LSAHPVPVL,CHLAVRTSM,VRTSMLTLL,VPLGSILCL, QECGRRASV,TPPSTPMII,RTSMLTLLPM,CLAGSLSTMA,AMPSAM GVAL,SIMMSWMPPL,IMMSWMPPLA,WMPPLAPCAA,KTFGVPLGSI, SQAPPGSQSI,TLCPAHPARA,HLAVRTSMLT,AVRTSMLTLL,NLRRGY PRLK,WVNLRRGYPR,STPMIISTTR,RGYPRLKTFG,RLKTFGVPLG,ST MAPTPPST,CGRRASVPCR,RASVPCRPMI,SARPGPWRTS,PWRTSAMP SA,RTSAMPSAMG,SWMPPLAPCA,QQWVNLRRGY,PTLCPAHPAR,VLS GCHLAVR,MAPTPPSTPM,TSAMPSAMGV,YPRLKTFGVP,APTPPST PMI,RPMIGSARPG,RPGPWRTSAM,APPGSQSIMM,APTLCPAHPA, CPAHPARAPT,TPLSAHPVPV,RRGYPRLKTF,LCLAGSLSTM, RQECGRRASV,RRASVPCRPM,MIGSARPGPW,WRTSAMP SAM,SAMPSAMGVA,RMPPSGSQAP,MMSWMPPLAP,A RAPTAVPAF,GCHLAVRTSM,CHLAVRTSML,LAVRTSMLTL, MPSAMGVALP,MPPLAPCAAC,SPAPTLCPAH,VPAFTPLSA H,HPVPVLSGCH,CESGRSPPAT,VPLGSILCLA,VPVLSGCHL A PLEKH c.436T>C p.S146 TALLEANSTPAPAGATVPPRSRRVC[p.S RSRRVCPKV,RVCPKVRCV,CPKVRCVT,RSRRVCPKVR CLL B1 P 146P]PKVRCVTRSWSPCKVERRIWVRV YSP PLEKH c.1150G>A p.E384 AIIFLQNSFCSLNTHRTPRTAQEVA[p.E3 KLIDQHETM,RTAQEVAKL,KLIDQHETMM,AKLIDQHETM CRC G4B K 84K]KLIDQHETMMKLVLEDPLLVSLRLE G PLEKH c.2684C>T p.A895 RIIHNWDLTKRPICRQALKFLTQIR[p.A8 TQIRVQPLI,LTQIRVQPL,LKFLTQIRV,IRVQPLINL,VQPLINL TGCT M1 V 95V]VQPLINLQMVNASLYEHVERMHLI QM,FLTQIRVQPL,ALKFLTQIRV,QIRVQPLINL,RVQPLINLQ GR M PLEKH c.1376C>T p.S459 DQSFRTGSPGDAPERPPLCDFSEGL[p.S LLAPMDFYR,LAPMDFYRF,GLLAPMDFY,FSEGLLAPM,LLA BLCA M2 L 459L]LAPMDFYRFTVESPSTVTSGGGFI PMDFYRF,GLLAPMDFYR,SEGLLAPMDF,DFSEGLLAPM HDP PLEKH c.761de|C p.T254f QPSADRASSLSRPWEKTDKGATYTP[p. ATYTPRHPR,ATYTPRHPRS,GATYTPRHPR STAD O1 s T254fs]RHPRS* PLEKH c.1051G>C p.E351 GEMQASGPPAPGTVQVSVNGMDDSP GMDDSPQPA,GMDDSPQPAK,SPQPAKPSQA CESC O2 Q [p.E351Q]QPAKPSQAEGTPGTPPKDA TTSTALP PLIN5 c.916C>T p.R306 LETLVLSRSLTQELQGTVEALESSV[p.R3 ALESSVWGL,ESSVWGLPA,SVWGLPAGA,VEALESSVW,EA ACC W 06W]WGLPAGAQEKVAEVRRSVDALQ LESSVWGL,SSVWGLPAGA,LESSVWGLPA TAFA PLK1 c.698A>G p.D233 KKTLCGTPNYIAPEVLSKKGHSFEV[p.D SFEVGVWSI,KGHSFEVGV,GVWSIGCIM,FEVGVWSIG,GV CRC G 233G]GVWSIGCIMYTLLVGKPPFETSCL WSIGCIMY,HSFEVGVWSI,EVGVWSIGCI,KGHSFEVGVW, KE VGVWSIGCIM,FEVGVWSIGC PLOD c.888_889i p.P296fs GWTPEGGCGFCNQDRRTLPGGQPPP[p.P2 RVCGTAYSV,SVSAPLPAA,SGRVCGTAY,AATPGLSPR,TAYS STAD 3 nsC 96fs]PGVSGRVCGTAYSVSAPLPA VSAPL,YSVSAPLPA,APLPAAAAT,LPAAAATPG,LSPRQGHP AAATPGLSPRQGHPFPAQQRGLP* F,RQGHPFPAQ,VSGRVCGTAY,GTAYSVSAPL,SVSAPLPAA A,AAATPGLSPR,YSVSAPLPAA,LPAAAATPGL,SPRQGHPF PA,HPFPAQQRGL,GLSPRQGHPF,GRVCGTAYSV PLOD c.889de|C p.R297fs GWTPEGGCGFCNQDRRTLPGGQPPP[p. FWPCLWNSL,CLWNSLLRF,NSLLRFCPA,TTRSSMNPT,RSS CRC,STAD 3 R297fs]GCFWPCLWNSLLRFCPASCS MNPTSL,RSSRTTSQL,SPFSCTTTR,SLTPGRSSR,TIPPTGSPF, GCYSWTIPPTGSPFSCTTTRSSMNPTSL CPASCSGCY,ASCSGCYSW,SCTTTRSSM,SMNPTSLTP,WP TPGRSSRTTSQL* CLWNSLL,CFWPCLWNSL,FWPCLWNSLL,WTIPPTGSPF,T TRSSMNPTS,RSSMNPTSLT,TSLTPGRSSR,MNPTSLTPGR,F SCTTTRSSM,TRSSMNPTSL,SMNPTSLTPG,GRSSRTTSQL PLSCR c.229G>A p.E77K FPSPGPVALGSAAPFLPLPGVPSGL[p.E KFLVQIDQI,VPSGLKFLV,GVPSGLKFLV,KFLVQIDQIL,LPGV CRC 3 77K]KFLVQIDQILIHQKAERVETFLGWE PSGLKF,LKFLVQIDQI T PLXNA c.3046de|C p.P1016fs LTPPGQSPGSAPIIININRAQLTNP[p.P1 INRAQLTNPR STAD 1 016fs]R* PLXNA c.3883G>A p.E129 ALECKEAFAELQTDIHELTNDLDGA[p.E ASIPFLDYR,GASIPFLDY,DLDGASIPF,GASIPFLDYR,SIPFLD UCEC 1 5K 1295K]SIPFLDYRTYAMRVLFPGIEDHP YRTY,LTNDLDGASI,NDLDGASIPF VLK PLXNA c.1392_139 p.P464fs YNGYSVVFVGTKSGKLKKIRADGPP[p.P STRWSLCSR,KIRADGPPP,SATCTSCLR,WPSPLISAT,SPWS STAD 2 3insCC 464fs]PMVGSSTRWSLCSRTEAPSSGT HVSSI,IRADGPPPM,PMVGSSTRW,VGSSTRWSL,TEAPSS WPSPLISATCTSCLRDRSPGSPWSHVSS GTW,ISATCTSCL,RDRSPGSPW,WSHVSSIRL,SPGSPWSHV, IRLVGSA* LISATCTSCL,SSTRWSLCSR,ISATCTSCLR,KIRADGPPPM,S TRWSLCSRT,RWSLCSRTEA,MVGSSTRWSL,RTEAPSSGT W,WPSPLISATC,PPMVGSSTRW PLXNA c.172C>T p.P58S LTHLAVHRVTGEVFVGAVNRVFKLA[p. KLASNLTEL,RVFKLASNL,LASNLTELR,KLASNLTELR,RVFKL HNSC 3 P58S]SNLTELRAHVTGPVEDNARCYPP ASNLT,FKLASNLTEL PSM PLXNC c.1385C>T p.S462 IYIYLTAGKEVRRIRVANCNKHKSC[p.S4 NKHKSCLECL CRC 1 L 62L]LECLTATDPHCGWCHSLQRCTFQ GDC PLXNC c.2455C>T p.R819 NINVSEYCVATYCGFLAPSLKSSKV[p.R8 KVCTNVTVK,CTNVTVKLR,KSSKVCTNV,SKVCTNVTV,SSKV CRC 1 C 19C]CTNVTVKLRVQDTYLDCGTLQYRE CTNVTV DP PLXN c.1100G>T p.R367 GLQCAGGAGRGDLYSRLVSVFPARE[p. VFPARELLF,SVFPARELL,ELLFAVFER,ARELLFAVF,FPARELL TGCT D1 L R367L]LLFAVFERPQGSPAARAAPAAL FA,RELLFAVFE,SVFPARELLF,FPARELLFAV,PARELLFAVF CAFR PMEP c.624de|C p.P208f RAPPNRTIFDSDLMDSARLGGPCPP[p. RLGGPCPPA,AVTRASAPR,ATAAAGAWR,SSTSRAVGR,AV STAD A1 s P208fs]AVTRASAPRATAAAGAWRGR GRPPCWR,VTRASAPRA,RASAPRATA,AWRGRRPPT,RGR RPPTARSSATTRGPPSSTSRAVGRPPC RPPTAR,TARSSATTR,AAGAWRGRR,SAPRATAAA,APRAT WRGPGSTTHTSRP* AAAG,RPPTARSSA,RPPCWRGPG,RATAAAGAW,RAVGRP PCW,RLGGPCPPAV,VTRASAPRAT,RASAPRATAA,ASAPR ATAAA,RATAAAGAWR,AWRGRRPPTA,RGRRPPTARS,TS RAVGRPPC,RAVGRPPCWR,TAAAGAWRGR,AAAGAWRG RR,CPPAVTRASA,APRATAAAGA,RPPTARSSAT,GPPSSTS RAV,ARLGGPCPPA PMS2 c.1952A>G p.K651 AKRIKQLHHEAQQSEGEQNYRKFRA[p. NYRKFRARI,KFRARICPG,RARICPGEN,QNYRKFRAR,KFRA TGCT R K651R]RICPGENQAAEDELRKEISKTMF RICPGE,RARICPGENQ,EQNYRKFRAR,RKFRARICPG AEM PNKP c.520G>T p.G174 NLEKLLVFTAAGVKPQGKVAGFDLD[p. AGFDLDWTL,WTLITTRSGK,DLDWTLITTR,GKVAGFDLDW LUAD W G174W]WTLITTRSGKVFPTGPSDWRIL YPEI PNLIP c.110C>T p.T37M GAVAGKEVCYERLGCFSDDSPWSGI[p. GIMERPLHI,SPWSGIMER,IMERPLHIL,GIMERPLHIL,DSP MM T37M]MERPLHILPWSPKDVNTRFLLYT WSGIMER,MERPLHILPW NEN PNPLA c.668T>C p.L223 LDLYVNIAKQDIMLSLANLVRLNQA[p.L NQAPFPPSK,LVRLNQAPF,LNQAPFPPSK,NQAPFPPSKR,A TGCT 4 P 223P]PFPPSKRKMESLYQCGFDDTVKF PFPPSKRKM,NLVRLNQAPF,RLNQAPFPPS LLK PNPLA c.3597de|C p.P119 LAYVCCVRQLEVVKSSDYCEYLRPP[p.P YLRPPSTAT,CLTSGAAAA,TLPKLCLAL,GMHTQTSRA,WLS STAD 7 9fs 1199fs]STATAPWTSASSTRSAKWATST QNCLRA,SQNCLRAPL,SASSTRSAK,STRSAKWAT,KWATST GARCLTSGAAAACWRRCSATSRGRARS GAR,GARCLTSGA,AACWRRCSA,RGRARSPRV,RARSPRVR PRVRSSPVPTPPSRTLPKLCLALSPPSPP S,RVRSSPVPT,RTLPKLCLA,TTRRSTRRS,STRRSCWTS,RSC WWMTNLTTRRSTRRSCWTSPGMHTQ WTSPGM,TSRAPQPSR,LTRTGRGLC,SATSRGRAR,WWMT TSRAPQPSRAQTWRTSPHCGIDTPVWL NLTTR,WMTNLTTRR,NLTTRRSTR,LTTRRSTRR,VWLSQNC SQNCLRAPLTRTGRGLC* LR,RAPLTRTGR,TATAPWTSA,ATAPWTSAS,APWTSASST, SPRVRSSPV,VPTPPSRTL,SPPWWMTNL,APQPSRAQT,RS AKWATST,AKWATSTGA,ALSPPSPPW,AQTWRTSPH,PPS TATAPW,CEYLRPPST,YLRPPSTATA,TSASSTRSAK,RTLPKL CLAL,STATAPWTSA,STRSAKWATS,SAKWATSTGA,GARC LTSGAA,AAACWRRCSA,CWRRCSATSR,TSRGRARSPR,RG RARSPRVR,RARSPRVRSS,RSPRVRSSPV,RVRSSPVPTP,RS SPVPTPPS,TTRRSTRRSC,STRRSCWTSP,TSRAPQPSRA,RA QTWRTSPH,TWRTSPHCGI,CSATSRGRAR,WWMTNLTTR R,TNLTTRRSTR,NLTTRRSTRR,QTSRAPQPSR,PVWLSQNC LR,WTSASSTRSA,RPPSTATAPW,TPPSRTLPKL,APQPSRA QTW,SPHCGIDTPV,TPVWLSQNCL,APLTRTGRGL,CEYLRP PSTA,SASSTRSAKW,WATSTGARCL,LALSPPSPPW,ALSPP SPPWW,RRSCWTSPGM,AQTWRTSPHC,LSQNCLRAPL,S QNCLRAPLT,LTSGAAAACW PNRC c.217C>T p.R73C PRALPPTLFLPHFLGGDGPCLTPQP[p.R LTPQPCAPA,TPQPCAPAA,CLTPQPCAPA,TPQPCAPAAL CESC 1 73C]CAPAALPNRSLAVAGGTPRAAPKK RR PODN c.903de|C p.I301f RHVPKHLPPALYKLHLKNNKLEKIP[p.I3 LEKIPRGPSA STAD s 01fs]RGPSAS* PODN c.449C>T p.A150 QLQHLCVAHNKLSVAPQFLPRSLRV[p. FLPRSLRVV,RSLRVVDLA,VDLAANQVM,RVVDLAANQV,R GBM L1 V A150V]VDLAANQVMEIFPLTFGEKPAL SLRVVDLAA,LPRSLRVVDL RSVY PODX c.486_487i p.S162f TATAKPNTTSSQNGAEDTTNSGGKS[p. QPQCDHRPHI,SQPQCDHRPH GBM L nsC s S162fs]QPQCDHRPHIH* POGZ c.223G>T p.G75 SAPVPIAAHASVAGHLSTSTTVSSS[p.G TSTTVSSSW,STSTTVSSSW LUAD W 75W]WAQNSDSTKKTLVTLIANNNAG NPLV POLA c.1809G>T p.E603 PFQSHFCVVSKPKDCIFPYAFKEVI[p.E6 YAFKEVIDK,AFKEVIDKK,YAFKEVIDKK,EVIDKKNVKV CRC 1 D 03D]DKKNVKVEVAATERTLLGFFLAKV HK POLE c.1231G>T p.V411 EIGFQKDSQGEYKAPQCIHMDCLRW[p. HMDCLRWLK,RWLKRDSYL,IHMDCLRWL,LRWLKRDSY,L CRC,UCEC L V411L]LKRDSYLPVGSHNLKAAAKAKL KRDSYLPV,WLKRDSYLPV,IHMDCLRWLK,CLRWLKRDSY, GYDP HMDCLRWLKR,LRWLKRDSYL POLE c.1376C>T p.S459 YDPVELDPEDMCRMATEQPQTLATY[p. FVSDAVATY,ATYFVSDAV,QPQTLATYF,FVSDAVATYY,TLA CRC F S459F]FVSDAVATYYLYMKYVHPFIFAL TYFVSDA,ATYFVSDAVA,YFVSDAVATY,LATYFVSDAV,EQP CTI QTLATYF,QPQTLATYFV POLE c.1718G>T p.R573 ESGVFRSDIPCRFRMNPAAFDFLLQ[p.R FLLQLVEKT,DFLLQLVEK,AAFDFLLQL,AAFDFLLQLV,FLLQL LUAD L 573L]LVEKTLRHALEEEEKVPVEQVTNF VEKTL,QLVEKTLRHA,LQLVEKTLRH EE POLE c.857C>G p.P286 DDLVERPDPVVLAFDIETTKLPLKF[p.P2 TTKLPLKFR,RDAETDQIM,KFRDAETDQI,ETTKLPLKFR,RD UCEC R 86R]RDAETDQIMMISYMIDGQGYLIT AETDQIMM NRE POLM c.290de|C p.P97fs EETSAEEAVSWQERRMAAAPPGCTP[p. APPGCTPQL STAD P97fs]QLCWT* POLQ c.2579G>A p.R860 NAVPFKSARKAVDEEEEAVEERRNM[p. QTIWVTGRK,MQTIWVTGR,RNMQTIWVT,MQTIWVTGR CRC Q R860Q]QTIWVTGRKGLTEREAAALIVE K,NMQTIWVTGR,RNMQTIWVTG,EERRNMQTIW EARM POLR1 c.994A>C p.K332 IFSVESTGVLPPDVLVSEAIKVLMG[p.K3 KVLMGQCRR,VLMGQCRRF,LMGQCRRFL,VLMGQCRRFL, KIRC C Q 32Q]QCRRFLDELDAVQMD* AIKVLMGQCR,KVLMGQCRRF,GQCRRFLDEL POLR3 c.1114C>T p.L372 GDNKVDDRDYYGNKRLELAGQLLSL[p. LLSLFFEDL,SLFFEDLFK,LFFEDLFKK,LSLFFEDLF,FFEDLFKK BLCA B F L372F]FFEDLFKKFNSEMKKIADQVIPK F,LAGQLLSLF,AGQLLSLFF,QLLSLFFEDL,LSLFFEDLFK,SLFF QRA EDLFKK,LFFEDLFKKF,ELAGQLLSLF,LAGQLLSLFF,LLSLFFE DLF POM1 c.691C>A p.P231 GRRNLQPRPSAFKPLSKNGAVASFV[p. FVTRPGPLK,GAVASFVTR,SFVTRPGPL,SFVTRPGPLK,ASF LUAD 21L12 T P231T]TRPGPLKPSLGPWSLSFCDDAW VTRPGPL,NGAVASFVTR PSVL POM1 c.725C>A p.P242H FKPLSKNGAVASFVPRPGPLKPSLG[p.P SLGHWSLSF,KPSLGHWSL,PSLGHWSLSF,LKPSLGHWSL,G LUAD 21L12 242H]HWSLSFCDDAWPSVLVQPAPSA PLKPSLGHW IWDF PON1 c.917G>A p.R306 WVGCHPNGMKIFFYDSENPPASEVL[p. SEVLQIQNI,LQIQNILTE,PPASEVLQI,SEVLQIQNIL,NPPASE UCEC Q R306Q]QIQNILTEEPKVTQVYAENGTV VLQI LQGS POP1 c.2248de|A p.K750f VASSPNGKESDLRRSEVPCAPMPKK[p. LISHLMKWA,KLISHLMKW,KKLISHLMK,APMPKKLIS,MPK STAD s K750fs]LISHLMKWAHP* KLISHL,ISHLMKWAH,KLISHLMKWA,APMPKKLISH,MPKK LISHLM,KKLISHLMKW POST c.1522C>T p.R508 GAIHIFREIIKPAEKSLHEKLKQDK[p.R50 KQDKCFSTF,CFSTFLSLL,KCFSTFLSL,KQDKCFSTFL,LKQDK CRC N C 8C]CFSTFLSLLEAADLKELLTQPGDWTL CFSTF,KCFSTFLSLL POTE c.1519A>G p.K507 EEQNTGISQDEILTNKQKQIEVAEK[p.K AEKEMNSEL,KEMNSELSL,KEMNSELSLS,AEKEMNSELS GBM,PRAD C E 507E]EMNSELSLSHKKEEDLLRENSML QEE POTEE c.496G>A p.V166 DKLHRAAWWGKVPRKDLIVMLRDTD[p. MLRDTDMNKK GBM M V166M]MNKKDKQKRTALHLASANG NSEVVKL POTEE c.862G>A p.V288 ADIESKNKHGLTPLLLGVHEQKQQV[p. QVMKFLIKK,VMKFLIKKK,KQQVMKFLI,QQVMKFLIK,VHE LUAD M V288M]MKFLIKKKANLNALDRYGRTAL QKQQVM,EQKQQVMKF,QVMKFLIKKK,KQQVMKFLIK,Q ILAV QVMKFLIKK,GVHEQKQQVM,HEQKQQVMKF POTEE c.908G>T p.R303I LGVHEQKQQVVKFLIKKKANLNALD[p. IYGRTALIL,DIYGRTALI,KANLNALDI,ANLNALDIY,LDIYGRT UCEC R303I]IYGRTALILAVCCGSASIVSLLLEQ AL,ALDIYGRTAL,IYGRTALILA,KANLNALDIY,NLNALDIYGR, N KKANLNALDI POTEF c.2022G>T p.K674 STLREEIAMLRLELDTMKHQSQLRE[p.K SQLRENKYL,RENKYLEDI,KHQSQLRENK,HQSQLRENKY,N UCEC N 674N]NKYLEDIESVKKRNDNLLKALQL KYLEDIESV NEL POTEF c.334A>G p.S112 DDSAMKTLRNKMGKWCCHCFPCCRG[p. CCRGGSKSK TGCT G S112G]GSKSKVGAWGDYDDSAFME PRYHVRG POTE c.151G>A p.D51N KWCRHCFPWCRGSGKSNVGTSGDHD[p. DNSAMKTLR,NSAMKTLRSK SKCM G D51N]NSAMKTLRSKMGKWCRHCFP WCRGSS POTE c.407G>A p.R136 GSGKSKVGPWGDYDDSAFMEPRYHV[p. HVHREDLDK,FMEPRYHVH,FMEPRYHVHR GBM G H R136H]HREDLDKLHRAAWWGKVPR KDLIVML POU2 c.715A>G p.T239 RIKLGFTQGDVGLAMGKLYGNDFSQ[p. ATISRFEAL,DFSQATISR,FSQATISRF,KLYGNDFSQA,SQATI DLBCL F2 A T239A]ATISRFEALNLSFKNMCKLKPLL SRFFA,DFSQATISRF,YGNDFSQATI FKW POU2F2 c.715A>T p.T239S RIKLGFTQGDVGLAMGKLYGNDFSQ[p.T STISRFEAL,FSQSTISRF,DFSQSTISR,DFSQSTISRF,YGNDFS DLBCL 239S]STISRFEALNLSFKNMCKLKPLLE QSTI,SQSTISRFEA KW POU3F3 c.961G>T p.D321Y GGGGGAGPGLNSHDPHSDEDTPTSD[p.D YLEQFAKQF,DEDTPTSDY,TSDYLEQFAK,DYLEQFAKQF,TP LUAD 321Y]YLEQFAKQFKQRRIKLGFTQA TSDYLEQF DVGLA PPARGC1B c.403de|C p.P135fs AFPALDGGDALSCTSASPAPSSAPP[p.P KVNGLVLRR,LVLRRTAPK,SSAPPALPR,RSPRPQPLR,SSHC STAD 135fs]ALPRRSPRPQPLRWTSSHCCRSS CRSSS,HQALTPRRK,GARQASDLK,RTAPKTRRL,PALPRRSP SWPHPTQHQALTPRRKGPPGARQASD R,TQHQALTPR,APSSAPPAL,RPQPLRWTS,WPHPTQHQA, LKVNGLVLRRTAPKTRRLP* RRSPRPQPL,SHCCRSSSW,SPRPQPLRW,ASDLKVNGLV,GL VLRRTAPK,SSAPPALPRR,VLRRTAPKTR,RTAPKTRRLP,DLK VNGLVLR,SPAPSSAPPA,SPRPQPLRWT,RPQPLRWTSS,W PHPTQHQAL,TPRRKGPPGA,SSHCCRSSSW,SDLKVNGLVL PPIL4 c.1146T>A p.S382R PKQDTKYDLILDEQAEDSKSSHSHT[p.S KSSHSHTRK,SSHSHTRKK,HSHTRKKHK,HTRKKHKKK, CLL 382R]RKKHKKKTHHCSEEKEDEDYMPIK KSSHSHTRKK,HSHTRKKHKK,DSKSSHSHTR NT PPL c.1362de|C p.P454fs GESWELMDSAGNKLIAPAVCFVIPP[p. TLRPWLWLT,WLWLTAWAA,WLTAWAAST,FVIPPQTLR,C STAD P454fs]QTLRPWLWLTAWAASTGACG FVIPPQTL,PQTLRPWLW,NARCSSGMR,TAWAASTGA,RP RRQLGANARCSSGMRC* WLWLTAW,RQLGANARC,ANARCSSGM,IPPQTLRPW,TLR PWLWLTA,LTAWAASTGA,CGRRQLGANA,CFVIPPQTLR, WAASTGACGR,IPPQTLRPWL,RPWLWLTAWA,RQLGANA RCS,GANARCSSGM PPL c.976C>T p.H326Y DWKEYLNLLICEESHLKYMEDYHQF[p.H3 YMEDYHQFY,KYMEDYHQFY,HQFYEDVKDA,YEDVKDAQ BLCA 26Y]YEDVKDAQELLRKVDSDLNQKY EL GPDF PPM1E c.931C>T p.R311W IHLHVNLVRQEMFPHDPAEALCRAF[p. RAFWVTDER,AFWVTDERF,EALCRAFWV,AEALCRAFW, KIRC R311W]WVTDERFVQKAARESLRCGTT WVTDERFVQK,RAFWVTDERF,AEALCRAFWV GVVTF PPM1H c.678de|C p.P226fs NSRTLTRAASLRGGVGAPGSPSTPP[p.P SLPRRRFPM,SAWSSERLK,ASLPRRRFP,RLKVHSRKW,KVH STAD 226fs]HASLPRRRFPMSAWSSERLKVH SRKWTY,PMSAWSSER,MSAWSSERL,FPMSAWSSE,LPRR SRKWTYR* RFPMS,HASLPRRRF,RRRFPMSAW,MSAWSSERLK,KVHS RKWTYR,STPPHASLPR,ASLPRRRFPM,SERLKVHSRK,RLKV HSRKWT,FPMSAWSSER,SPSTPPHASL,LPRRRFPMSA,RRF PMSAWSS,LKVHSRKWTY PPP1R12C c.1116de|C p.P372fs LSSREKISLQDLSKERRPGGAGGPP[p.P ALRVPCSLK,PSRTRMRGK,RTRMRGKKV,RMRGKKVPP,RG STAD 372fs]SRTRMRGKKVPPNHPLQNPEPS KKVPPNH,ASPPRRTPA,SLKRPPSPG,SPPRRTPAL,RPPSPG MASPPRRTPALRVPCSLKRPPSPGALAS* ALA,KKVPPNHPL,LQNPEPSMA,SLKRPPSPGA,PSRTRMR GKK,RTRMRGKKVP,RMRGKKVPPN,MASPPRRTPA,ALRV PCSLKR,RPGGAGGPPS,HPLQNPEPSM,TPALRVPCSL,LKR PPSPGAL,GKKVPPNHPL,LQNPEPSMAS PPP2R1A c.536C>G p.P179R CYPRVSSAVKAELRQYFRNLCSDDT[p.P1 TRMVRRAAA,RMVRRAAAS,NLCSDDTRMV,RMVRRAAAS UCEC,UCS 79R]RMVRRAAASKLGEFAKVLELDNVKSE K,RNLCSDDTRM PPP2R1A c.547C>T p.R183W VSSAVKAELRQYFRNLCSDDTPMVR[p. MVRWAAASK,DTPMVRWAA,TPMVRWAAA,VRWAAASK CRC,UCS R183W]WAAASKLGEFAKVLELDNVKSE L,CSDDTPMVRW,MVRWAAASKL,DTPMVRWAAA,TPMV IIPM RWAAAS,WAAASKLGEF PPP2R1A c.656C>T p.S219L KVLELDNVKSEIIPMFSNLASDEQD[p.S DEQDLVRLL,NLASDEQDLV,DEQDLVRLLA UCS 219L]LVRLLAVEACVNIAQLLPQEDLEA LV PPP2R1A c.767C>T p.S256F IAQLLPQEDLEALVMPTLRQAAEDK[p.S KFWRVRYMV,FWRVRYMVA,QAAEDKFWR,RQAAEDKF UCEC 256F]FWRVRYMVADKFTELQKAVGPE W,DKFWRVRYM,KFWRVRYMVA,QAAEDKFWRV,TLRQA ITKT AEDKF,AEDKFWRVRY PPP2R2B c.977C>T p.P326L SKGTIRLCDMRASALCDRHTKFFEE[p.P RHTKFFEEL,LEDPSNRSF,ELEDPSNRSF,LEDPSNRSFF CRC 326L]LEDPSNRSFFSEIISSISDVKFSHSG PPP2R c.1165de|A p.T389fs RKVQKEGKISYADFVWFLISEEDKK[p.T WTWSSRGLK,CSSSSTSTR,STGSAAWTW,SSTSTRSSA,RTA 3B 389fs]HRPASSTGSAAWTWTGTAPCP SARCWT,SARCWTWSS,EGWTAWPSR,WTWTGTAPC,WT STAD CSSSSTSTRSSAEGWTAWPSRPCPSRT AWPSRPC,RPASSTGSA,RPCPSRTAS,SSAEGWTAW,KKHR ASARCWTWSSRGLKGRSRCRT* PASST,ASSTGSAAW,RSSAEGWTA,AEGWTAWPS,TASAR CWTW,RTASARCWTW,SSSTSTRSSA,SARCWTWSSR,CW TWSSRGLK,SSRGLKGRSR,RGLKGRSRCR,TWSSRGLKGR,S AAWTWTGTA,RPASSTGSAA,RPCPSRTASA,SSTGSAAWT W,RSSAEGWTAW,RCWTWSSRGL,SEEDKKHRPA PPP2R c.930C>A p.F310 ELRRSSFLQNVALLEEEADINQLTE[p.F3 LTELFSYEH,NQLTELFSY,ELFSYEHFY,ADINQLTEL,TELFSYE UCEC 3B L 10L]LFSYEHFYVIYCKFWELDTDHDLLID HF,ELFSYEHFYV,LFSYEHFYVI,INQLTELFSY,ADINQLTELF,L TELFSYEHF,TELFSYEHFY PPP2R c.776C>A p.S259 GFALPLKEEHKIFLLKVLLPLHKVK[p.S25 YLSVYHPQL,KYLSVYHPQ,KVKYLSVYH,LPLHKVKYL,LHKVK CRC 5C Y 9Y]YLSVYHPQLAYCVVQFLEKDSTLTEP YLSV,HKVKYLSVY,YLSVYHPQLA,LLPLHKVKYL,KYLSVYHP QL,KVKYLSVYHP,VLLPLHKVKY,LHKVKYLSVY,HKVKYLSVY H PPP4R c.1791G>C p.L597 DSVPLISDAVENMDSTLHYIHSDSD[p.L HYIHSDSDF,SDFSNNSSF,LHYIHSDSDF CESC 1 F 597F]FSNNSSFSPDEERRTKVQDVVPQ ALL PPP6C c.901C>T p.R301 LVHEGYKFMFDEKLVTVWSAPNYCY[p. CYCCGNIASI,YCCGNIASIM SKCM C R301C]CCGNIASIMVFKDVNTREPKLF RAVP PPT2 c.794G>T p.R265 WQSSFFGFYDANETVLEMEEQLVYL[p. YLLDSFGLK,VYLLDSFGL,QLVYLLDSF,MEEQLVYLL,LVYLLD LUAD L R265L]LDSFGLKTLLARGAIVRCPMAGI SFGL,YLLDSFGLKT,LLDSFGLKTL,EQLVYLLDSF SHT PRAM c.802G>A p.A268 QPEFSEAAQTPLWKPQSSEPKRDSS[p. RDSSTFPKK,EPKRDSSTF,SEPKRDSSTF UCEC 1 T A268T]TFPKKASQPPLSDFPKKPPQPEL GDL PRAM c.251G>C p.C84S KLQVLDLQDVCENFWMVWSEAMAH MAHGSFLNA,SFLNAKRNK,HGSFLNAKR,EAMAHGSFL,SE SKCM EF11 G[p.C84S]SFLNAKRNKTPVQDCPRMR AMAHGSF,AMAHGSFLNA,MAHGSFLNAK,GSFLNAKRNK, ERQPLTV WSEAMAHGSF,SEAMAHGSFL PRAM c.311G>A p.R104 AMAHGCFLNAKRNKTPVQDCPRMRE[p. RMREQQPLT,EQQPLTVFV,REQQPLTVF,RMREQQPLTV,C CLL EF11 Q R104Q]QQPLTVFVELWLKNRTLDEY PRMREQQPL,MREQQPLTVF,REQQPLTVFV LTCLLL PRAM c.743G>A p.R248 LTQFTPYLGHMRNLQKLILSHMDVS[p. LSHMDVSHY,SHMDVSHYV,VSHYVSPEQK,ILSHMDVSHY, CRC EF4 H R248H]HYVSPEQKKEIVTQFTTQFLKLR LSHMDVSHYV CLQ PRAM c.1342A>G p.I448V ALCWGRFAELGAELMKTPRDLRQPK[p. LRQPKVIVF,TPRDLRQPKV,DLRQPKVIVF,QPKVIVFCTV TGCT EF8 I448V]VIVFCTVPCPRCGIRASYDLEPSH CL PRAM c.956G>A p.R319 LEMVVMTDCLLSESDLKHLSWCPSI[p. SWCPSIHQL,HLSWCPSIH,SWCPSIHQLK,CPSIHQLKEL,LS PRAD EF8 H R319H]HQLKELDLRGVTLTHFSPEPLTG WCPSIHQL LLE PRB1 c.820de|C p.R274fs KPQGPPPPGKPQGPPAQGGSKSQSA[p. HPNKKATIL,VPHLQQEAI,IPSSLRHLL,SPRDHHALL,LPDLPS HNSC R274fs]DLLQESHKDHPNKKATILKVPH DSL,DSLPSHLGF,SKSQSADLL,LQQEAIPSS,QQEAIPSSL,LP LQQEAIPSSLRHLLLDSPRDHHALLKGA SDSLPSH,LQQEAIPSSL,AIPSSLRHLL,LLKGADLPDL,SADLL DLPDLPSDSLPSHLGFNDRK* QESHK,SPRDHHALLK,EAIPSSLRHL,IPSSLRHLLL,LPSDSLPS HL,KKATILKVPH,LKVPHLQQEA,SDSLPSHLGF PRDM c.1763C>G p.S588 PYPLKKQNGKIKYECNVCAKTFGQL[p.S KTFGQLCNL,GQLCNLKVH,KTFGQLCNLK,QLCNLKVHLR,A MM 1 C 588C]CNLKVHLRVHSGERPFKCQTCNK KTFGQLCNL,GQLCNLKVHL GFT PRDM c.3107C>T p.P103 HLCNRCFGQQTNLDRHLKKHEHENA[p. ALVSQHPGV,KKHEHENAL,HEHENALVS,HENALVSQH,AL LUAD 16 6L P1036L]LVSQHPGVLTNHLGTSASSPT VSQHPGVL,LKKHEHENAL,KKHEHENALV SESDN PRDM c.811G>C p.E271 RRHKKYTCGSVGAALYEGLAEELKP[p.E AEELKPQGL BLCA 16 Q 271Q]QGLGGGSGQAHECKDCERMFP NKYSL PRDM c.2404T>A p.*802 DSVGTEDCRINSAVYSADESLSAHK[p. KIHITSYLL,SAHKKKEKK,NGKIHITSY,GKIHITSYL,ILDENAN CLL 4 K 802K]KKEKKQAILDENANGKIHITSYLL* GKI,SLSAHKKKEK,AILDENANGK,ANGKIHITSY,NGKIHITSY L,GKIHITSYLL PRDM c.1159A>C p.M38 GQELGIRSSIEPAESLGQAVNCWSG[p. SGLGMSMAR,QAVNCWSGL,VNCWSGLGM,CWSGLGMS PRAD 7 7L M387L]LGMSMARNWASSGAASGRKS M,LGMSMARNW,GQAVNCWSGL,AVNCWSGLGM,NCW SWQGEN SGLGMSM PRELP c.601G>T p.D201 LRLSQNHISRIPPGVFSKLENLLLL[p.D20 KLENLLLLY,LLYLQHNRL,LLLYLQHNR,LENLLLLYL,KLENLLL LUAD Y 1Y]YLQHNRLSDGVFKPDTFHGLKNLM LYL,LLLYLQHNRL,SKLENLLLLY,LLLLYLQHNR QL PREP c.1407C>A p.F469 SKDGTKIPMFIVHKKGIKLDGSHPA[p.F KLDGSHPAL,SHPALLYGY,ALLYGYGGF,KLDGSHPALL,LLY CESC L 469L]LLYGYGGFNISITPNYSVSRLIFVR GYGGFNI,GSHPALLYGY,LDGSHPALLY,IKLDGSHPAL H PREX1 c.2191G>A p.V731I AKEIIKIPDQPDTLCFQIRGAAPPY[p.V7 AAPPYIYAV,RGAAPPYIY,GAAPPYIYAV,QIRGAAPPYI,RGA CRC 31I]IYAVGRGSEAMAAGLCAGQCILKV APPYIYA,IRGAAPPYIY NG PREX1 c.3736G>A p.E124 CLEHLFNQVDSINALLKGPVMSRAF[p.E MSRAFKETK,FKETKHFPM,RAFKETKHF,VMSRAFKETK,KG UCEC 6K 1246K]KETKHFPMNHSLQEFKQKEECT PVMSRAFK,MSRAFKETKH,AFKETKHFPM,SRAFKETKHF IRGR PREX2 c.1088G>A p.R363 WFVCMAKTPEEKHEWFEAILKERER[p. ILKERERQK,RQKGLKLGM,KERERQKGL,RERQKGLKL,AILK BRCA Q R363Q]QKGLKLGMEQDTWVMISEQG ERERQK,KERERQKGLK EKLYKM PREX2 c.1686_168 p.R562f CDNGFMHHVLEKSEFKDEPLLFRFF[p.R EPLLFRFFF,DEPLLFRFFF STAD 7insT s 562fs]FG* PRG4 c.2023A>C p.N675 PTTPEEPTPTTPEEPAPTTPKAAAP[p.N KAAAPHTPK,APHTPKEPA CLL H 675H]HTPKEPAPTTPKEPAPTTPKEPAP TT PRIC2 c.3865G>C p.E128 LFWVQIVLWRQGFYYPLGIVREVLP[p.E IVREVLPQA,REVLPQAST,EVLPQASTW,GIVREVLPQA,QA BLCA 85 9Q 1289Q]QASTWEQGLRILGLEYSLRVPP STWEQGLR,REVLPQASTW SDQA PRKA c.1220G>A p.R407 CPLDALNTTKPKSLAVKKAKWHLGI[p.R GIQSQSKPY,KAKWHLGIQS,LGIQSQSKPY,IQSQSKPYDI CRC A2 Q 407Q]QSQSKPYDIMAEVYRAMKQLDF EWKV PRKA c.311C>A p.P104 PTVFRWTGGGKEVYLSGSFNNWSKL[p. NWSKLHLTR,HLTRSHNNF,FNNWSKLHL,SKLHLTRSH,HLT CLL B1 H P104H]HLTRSHNNFVAILDLPEGEHQY RSHNNFV,SFNNWSKLHL,NNWSKLHLTR,LHLTRSHNNF KFFV PRKA c.926C>T p.S309 ERLKVVDVIGTKVYNDGEQIIAQGD[p.S DLADSFFIV,AQGDLADSF,GDLADSFFI,AQGDLADSFF,IAQ CRC R2B L 309L]LADSFFIVESGEVKITMKRKGKSE GDLADSF,GEQIIAQGDL,GDLADSFFIV VE PRKC c.1294de|G p.G432fs FLTHLICTFQTKDHLFFVMEFLNGG[p.G FVMEFLNGGT GBM D 432fs]T* PRKCE c.470_471 p.Q157fs SSGEAPKDNEERVFRERMRPRKRQG[p. HLSSAAHLL,YLLRSLWVP,GTLAAGFAV,QVHGHLSSA,SLHL KIRC insG Q157fs]GRQAQGPSGQRPQVHGHLSS RGPQA,LLRSLWVPA,RLHLGCHRK,AVPRAHNHK,PYLLRSL AAHLLLPLQRLHLGCHRKAGIPVSSLHL WV,LWVPALGTL,RPRKRQGGR,HNHKVCWVK,VQRQHAP RGPQAVPRAHNHKVCWVKEAGDPRP QV,RQHAPQVRY,RSLWVPALG,RYPQLQGPY,WVKEAGDP GGLPAVQRQHAPQVRYPQLQGPYLLR R,QLQGPYLLR,SAAHLLLPL,GPSGQRPQV,RPQVHGHLS,V SLWVPALGTLAAGFAV* PRAHNHKV,DPRPGGLPA,APQVRYPQL,YPQLQGPYL,VPA LGTLAA,ALGTLAAGF,RKRQGGRQA,GQRPQVHGH,HGHL SSAAH,GHLSSAAHL,LSSAAHLLL,LQRLHLGCH,CHRKAGIP V,KAGIPVSSL,LHLRGPQAV,RAHNHKVCW,PQLQGPYLL,G PYLLRSLW,LRSLWVPAL,HLSSAAHLLL,LLLPLQRLHL,SLHL RGPQAV,YLLRSLWVPA,LLRSLWVPAL,SLWVPALGTL,ALG TLAAGFA,AAHLLLPLQR,RYPQLQGPYL,RMRPRKRQGG,L QRLHLGCHR,RLHLGCHRKA,SSLHLRGPQA,HLRGPQAVPR, QAVPRAHNHK,RAHNHKVCWV,VQRQHAPQVR,VRYPQL QGPY,SSAAHLLLPL,RPQVHGHLSS,VPRAHNHKVC,DPRPG GLPAV,YPQLQGPYLL,GPYLLRSLWV,HLGCHRKAGI,GQRP QVHGHL,HGHLSSAAHL,GHLSSAAHLL,RKAGIPVSSL,AGIP VSSLHL,RQHAPQVRYP,LQGPYLLRSL,VPALGTLAAG PRKC c.1033C>T p.R345 SSSPIPSPSPSPTDPKRCFFGASPG[p.R3 CLHISDFSF,CLHISDFSFL,SPGCLHISDF,GCLHISDFSF STAD G C 45C]CLHISDFSFLMVLGKGSFGKVMLA ER PRKCI c.1438C>T p.R480 IVGSSDNPDQNTEDYLFQVILEKQI[p.R KQICIPRSL,CIPRSLSVK,KQICIPRSLS,LEKQICIPRS CRC C 480C]CIPRSLSVKAASVLKSFLNKDPKER L PRKC c.971C>T p.A324 GMNVHHRCQTKVANLCGINQKLMAE[p. KLMAEVLAM,LMAEVLAMI,NQKLMAEVL,AEVLAMIES,GI UCEC Q V A324V]VLAMIESTQQARCLRDTEQIF NQKLMAEV,KLMAEVLAMI,QKLMAEVLAM,AEVLAMIEST REGPV PRKD c.10702C> p.Q356 DTSTGHKNKEFVARIKSKLDQGGVI[p.Q GVIEDFINA,GVIEDFINAL CESC C G 8E 3568E]EDFINALDQLSNPELLFKDWSN DVRA PRKR c.366G>T p.K122 NILKANASICFAVPDPLMPDPSKQP[p.K QPNNQLNPI,KQPNNQLNPI CRC A N 122N]NNQLNPIGSLQELAIHHGWRLPE YTL PRMT c.84de|C p.S28fs SSRCLLLRRKMAENAAESTEVNSPP[p.S LLSPCNASI,SIMCPLNPA,IMCPLNPAA,SPPSPSSLL,LSPCN STAD 8 28fs]PSPPSPSSLLSPCNASIMCPLNPAA ASIM,SLLSPCNASI,SIMCPLNPAA,LLSPCNASIM,PPSPPSP QDGARCPSC* SSL PRMT c.91T>C p.S31P SSRCLLLRRKMAENAAESTEVNSPP[p.S SPPPQPPQPV BLCA 8 31P]PQPPQPVVPAKPVQCVHHVSTQP SCP PROD c.1579C>G p.L527 TVRFALRRMEELGLHPADHRVYFGQ[p. VYFGQVLGM,RVYFGQVLG,HRVYFGQVL,RVYFGQVLGM, TGCT H V L527V]VLGMCDQISFPLGQAGYPVYKY VLGMCDQISF,GQVLGMCDQI VPYG PROK c.889G>A p.V297I KTVLVLMCILTAYVLCWAPFYGFTI[p.V IIRDFFPTV,GFTIIRDFF,TIIRDFFPT,APFYGFTII,YGFTIIRDF,I GBM R2 297I]IRDFFPTVFVKEKHYLTAFYVVECI RDFFPTVF,TIIRDFFPTV,FYGFTIIRDF,YGFTIIRDFF,APFYGF A TIIR,FTIIRDFFPT,IIRDFFPTVF PROX c.1774de|T p.F592f SPYSGSAMQEGLSPNHLKKAKLMFF[p. KLMFFIPVI,FIPVIPAPI,KAKLMFFIP,MFFIPVIPA,KKAKLMF STAD 1 s F592fs]IPVIPAPIC* FI,AKLMFFIPV,LMFFIPVIPA,FFIPVIPAPI,KAKLMFFIPV,AK LMFFIPVI PROX c.674T>A p.V225 PRESYRENKRKQKLPQQQQQSFQQL[p. SFQQLDSAR,QSFQQLDSAR KIRC 1 D V225D]DSARKEQKREERRQLKQQLED MQKQL PRPF3 c.865C>T p.R289 STSVLPHTGYIYHSDIVQSLPPDLR[p.R2 RWKAARLVA,DLRWKAARL,WKAARLVAA,LRWKAARLV,L TGCT 1 W 89W]WKAARLVAAKCTLAARVDSFHES PPDLRWKA,SLPPDLRWKA,QSLPPDLRWK,RWKAARLVAA, TEG DLRWKAARLV,VQSLPPDLRW,LRWKAARLVA,LPPDLRW KAA PRPF6 c.2288G>T p.R763 KCPHSTPLWLLLSRLEEKIGQLTRA[p.R7 QLTRALAIL,KIGQLTRAL,GQLTRALAI,ALAILEKSRL,LTRALA LUAD L 63L]LAILEKSRLKNPKNPGLWLESVRLE ILEK,KIGQLTRALA,RALAILEKSR,EKIGQLTRAL,GQLTRALAI Y L PRRC2 c.5647C>A p.P188 SASIPILASALASTSAPTPAPAASS[p.P18 AASSTAAPV,STAAPVITA,TPAPAASST,APAASSTAA,ASST KIRC C 3T 83T]TAAPVITAPTIPASAPTASVPLAPAS AAPVI,TAAPVITAPT,TPAPAASSTA,APAASSTAAP,AASSTA APVI PRRX1 c.587C>T p.A196 DVTAVEQPIVPRPAPRPTDYLSWGT[p. LSWGTVSPY,YLSWGTVSP,TVSPYSAMA,GTVSPYSAM,TD BRCA V A196V]VSPYSAMATYSATCANNSPAQ YLSWGTV,PTDYLSWGTV,YLSWGTVSPY,VSPYSAMATY,W GINMA GTVSPYSAM PRSS1 c.319G>A p.D107 EGNEQFINAAKIIRHPQYDRKTLNN[p.D TLNNNIMLI,KTLNNNIML,RKTLNNNIM,KTLNNNIMLI,TLN HNSC N 107N]NIMLIKLSSRAVINARVSTISLPTA NNIMLIK,NIMLIKLSSR,RKTLNNNIML P PRSS3 c.2038de|C p.L680f LPQGHQVSRLVISIRLPQHLGLRPP[p.L6 GLRPPWPSW,QHLGLRPPW,PQHLGLRPPW,LGLRPPWPS STAD 6 s 80fs]WPSWS* W PRSS5 c.115G>C p.E39Q TVATALMLPVKPPAGSWGAQIIGGH[p. AQIIGGHQV,QVTPHSRPY,HQVTPHSRPY,AQIIGGHQVT LUSC 7 E39Q]QVTPHSRPYMASVRFGGQHHC GGFLL PSD2 c.766de|G p.G256 NVLSRLSLMAMPNGFHEDGPQGPGG[p. GGMRMMMRR,GMRMMMRRT,RMMMRRTRT,MMMR STAD fs G256fs]MRMMMRRTRTSC* RTRTS,MMRRTRTSC,GPGGMRMMM,PQGPGGMRM,M MMRRTRTSC,GMRMMMRRTR,RMMMRRTRTS,GPQGP GGMRM,PQGPGGMRMM PSD3 c.1687A>C p.T563 PEIAFWGSNAGVKTTRLEAHSEMGS[p. MGSPEILEK,SEMGSPEIL,EMGSPEILEK,AHSEMGSPEI KIRC P T563P]PEILEKETPENLSNGTSSNVEAA KRL PSG8 c.1189C>T p.R397 FQLSGQKLFIPQITTKHSGLYACSV[p.R3 SVCNSATGK,GLYACSVCNS,CSVCNSATGK CRC C 97C]CNSATGKESSKSMTVKVSGKRIPV SL PSG8 c.958C>T p.R320 LILPSVTRNETGPYQCEIRDQYGGI[p.R3 DQYGGICSY,CSYPVTLNV,QYGGICSYPV,RDQYGGICSY,GG CRC C 20C]CSYPVTLNVLYGPDLPRIYPSFTYYR ICSYPVTL,CSYPVTLNVL PSG9 c.1210G>A p.E404 LFIPQITRNHSGLYACSVHNSATGK[p.E KISKSMTVK,SATGKKISK,KKISKSMTV,KISKSMTVKV,SVHN SKCM K 404K]KISKSMTVKVSGPCHGDLTESQS SATGKK * PSMD c.14C>T p.A5V MAAA[p.A5V]VVVEFQRAQSLLSTDRE MAAAVVVEF,AAAVVVEFQR TGCT 11 ASIDILHSI PSMD c.602G>A p.R201 SMEKKERVEFILEQMRLCLAVKDYI[p.R YIQTQIISK,IQTQIISKK,KDYIQTQII,AVKDYIQTQI,YIQTQIIS CRC 12 Q 201Q]QTQIISKKINTKFFQEENTEKLKLK KK,IQTQIISKKI Y PSME c.691C>T p.R231 IAKYPHVEDYRRTVTEIDEKEYISL[p.R23 SLWLIISEL,KEYISLWLI,EYISLWLII,DEKEYISLW,SLWLIISEL CESC 3 W 1W]WLIISELRNQYVTLHDMILKNIEKIK R,KEYISLWLII,ISLWLIISEL,DEKEYISLWL PSME c.1483A>G p.N495 GGRWFPEGPTHMLPLLMRALPGVDP[p. GVDPDDFSK,LPGVDPDDF,DDFSKCMITF,DPDDFSKCMI TGCT 4 D N495D]DDFSKCMITFQFIATFSTLVPL VDCS PSPH c.433G>A p.V145I IRELVSRLQERNVQVFLISGGFRSI[p.V1 SIIEHVASK,ISGGFRSII,SIIEHVASKL,LISGGFRSII,RSIIEHVA GBM 45I]IEHVASKLNIPATNVFANRLKFYFN SK,GFRSIIEHVA,IEHVASKLNI G PTCH1 c.2066C>A p.P689 LRTEYDPHTHVYYTTAEPRSEISVQ[p.P6 EISVQHVTV,SEISVQHVT,SEISVQHVTV,VQHVTVTQDT KIRC H 89H]HVTVTQDTLSCQSPESTSSTRDLLS Q PTCH1 c.3921de|C p.P130 RQQPHLDSGSLPPGRQGQQPRRDPP[p. FLLKGILAL,LLKGILALA,ILALAIGPA,ALAIGPAGA,LLKFLLKG STAD 7fs P1307fs]EKACGHPPTDRAETLLKFLL I,AIGPAGALA,ALAGPVLTT,ETLLKFLLK,KFLLKGILA,TQRPL KGILALAIGPAGALAGPVLTTLGTQRPLP PWAA,WAAPCPATA,LAIGPAGAL,RPLPWAAPC,LPWAAP WAAPCPATASPSPL* CPA,LKFLLKGIL,LKGILALAI,AGALAGPVL,LAGPVLTTL,LGT QRPLPW,AETLLKFLL,ILLKFLLKGI,FLLKGILALA,LLKGILALA I,ALAIGPAGAL,ALAGPVLTTL,KFLLKGILAL,HPPTDRAETL, GPAGALAGPV,CPATASPSPL,LLKFLLKGIL,TDRAETLLKF,LK FLLKGILA,TQRPLPWAAP,LPWAAPCPAT PTCH c.1764de|T p.F588f KKFCCFPFGSVPDEHGTDIHPISLF[p.F5 SLFLETILA,FLETILAPF,ILAPFSQGV,DIHPISLFL,ISLFLETIL,F STAD D3 s 88fs]LETILAPFSQGVSPSIL* SQGVSPSI,SQGVSPSIL,HPISLFLET,LETILAPFS,TILAPFSQG V,LFLETILAPF,HPISLFLETI,FSQGVSPSIL PTEN c.388C>G p.R130 CEDLDQWLSEDDNHVAAIHCKAGKG[p. GTGVMICAY,GGTGVMICAY,KAGKGGTGVM UCEC G R130G]GTGVMICAYLLHRGKFLKAQE ALDFY PTEN c.389G>A p.R130 CEDLDQWLSEDDNHVAAIHCKAGKG[p. QTGVMICAY,GKGQTGVMI,GQTGVMICAY,KAGKGQTGV CESC,CRC,UCEC Q R130Q]QTGVMICAYLLHRGKFLKAQE M ALDFY PTEN c.389G>C p.R130 CEDLDQWLSEDDNHVAAIHCKAGKG[p. PTGVMICAY,GKGPTGVMI,GPTGVMICAY,KAGKGPTGVM UCEC P R130P]PTGVMICAYLLHRGKFLKAQEA LDFY PTEN c.389G>T p.R130 CEDLDQWLSEDDNHVAAIHCKAGKG[p. LTGVMICAY,GLTGVMICA,KAGKGLTGV,GKGLTGVMI,GL UCEC L R130L]LTGVMICAYLLHRGKFLKAQEA TGVMICAY,KAGKGLTGVM LDFY PTEN c.407G>A p.C136 WLSEDDNHVAAIHCKAGKGRTGVMI[p. GVMIYAYLL,VMIYAYLLH,RTGVMIYAY,KGRTGVMIY,VMI GBM Y C136Y]YAYLLHRGKFLKAQEALDFYGE YAYLLHR,GVMIYAYLLH,KGRTGVMIYA,RTGVMIYAYL,GK VRTR GRTGVMIY,GRTGVMIYAY PTEN c.509G>A p.S170 FLKAQEALDFYGEVRTRDKKGVTIP[p.S VTIPNQRRY,NQRRYVYYY,IPNQRRYVY,GVTIPNQRRY,TIP GBM N 170N]NQRRYVYYYSYLLKNHLDYRPVA NQRRYVY,VTIPNQRRYV,IPNQRRYVYY LLF PTEN c.518G>A p.R173 AQEALDFYGEVRTRDKKGVTIPSQR[p. TIPSQRHYV,HYVYYYSYL,SQRHYVYYY,RHYVYYYSY,VTIPS GBM H R173H]HYVYYYSYLLKNHLDYRPVALLF QRHY,IPSQRHYVY,PSQRHYVYY,PSQRHYVYYY,VTIPSQRH HKM YV,RHYVYYYSYL,HYVYYYSYLL,SQRHYVYYYS,GVTIPSQRH Y,TIPSQRHYVY,QRHYVYYYSY,IPSQRHYVYY PTEN c.701G>T p.R234 GTCNPQFVVCQLKVKIYSSNSGPTR[p.R RLEDKFMYF,YSSNSGPTRL,TRLEDKFMYF,LEDKFMYFEF LUAD L 234L]LEDKFMYFEFPQPLPVCGDIKVEF FH PTEN c.795de|A p.L265f EFPQPLPVCGDIKVEFFHKQNKMLK[p. KMLKRTKCF,MLKRTKCFT,LKRTKCFTF,MLKRTKCFTF,KQN STAD s L265fs]RTKCFTFG* KMLKRTK,KMLKRTKCFT,NKMLKRTKCF PTEN c.830C>T p.T277I DIKVEFFHKQNKMLKKDKMFHFWVN[p. KMFHFWVNI,MFHFWVNIF,FHFWVNIFF,HFWVNIFFI,K GBM T277I]IFFIPGPEETSEKVENGSLCDQE MFHFWVNIF,MFHFWVNIFF,FHFWVNIFFI IDS PTGR c.119A>C p.E40A GYPTNSDFELKTAELPPLKNGEVLL[p.E4 VLLAALFLT,LLAALFLTV,EVLLAALFL,GEVLLAALF,VLLAALF TGCT 1 0A]AALFLTVDPYMRVAAKRLKEGDTM LTV,AALFLTVDPY,LKNGEVLLAA,GEVLLAALFL MG PTH2 c.64C>G p.L22V METRQVSRSPRVRLLLLLLLL[p.L22V]V LLLLLLVVV,LLVVVPWGV,LVVVPWGVR,LLLLVVVPW,RLLL PRAD VVPWGVRTASGVALPPVGVLSLRPP LLLLLV,LLLLLLLVVV,LLLVVVPWGV,LLVVVPWGVR,LLLLLV VVPW PTPDC c.1288C>T p.R430 AVAADFDNRGMIFSNEQQFDPLWKR[p. WKRWNVECL,WNVECLQPL,LWKRWNVECL,RWNVECLQ CRC 1 W R430W]WNVECLQPLTHLKRRLSYSD PL,QQFDPLWKRW SDLKRA PTPN1 c.1508G>T p.G503 IIREKGVDCDIDVPKTIQMVRSQRS[p.G QMVRSQRSV,MVRSQRSVM,RSVMVQTEA,VMVQTEAQY, LUAD 1 V 503V]VMVQTEAQYRFIYMAVQHYIETL SQRSVMVQT,IQMVRSQRSV,SVMVQTEAQY,MVRSQRS QRR VMV,QMVRSQRSVM PTPN1 c.226G>A p.E76K VTHIKIQNTGDYYDLYGGEKFATLA[p.E KLVQYYMEH,ATLAKLVQY,LAKLVQYYM,TLAKLVQYY,EKF MM 1 76K]KLVQYYMEHHGQLKEKNGDVIEL ATLAKL,TLAKLVQYYM,ATLAKLVQYY,FATLAKLVQY,GEKF KYP ATLAKL,KLVQYYMEHH PTPN1 c.2294G>A p.R765 PPTFSDKREQISENPTEATDIGFGN[p.R IGFGNQCGK CRC 2 Q 765Q]QCGKPKGPRDPPSEWT* PTPN1 c.2660C>T p.S887 SYQHKFQLQMRARQSNQDAQDIERA[p. RALFRSLNL,LFRSLNLQA,AQDIERALF,IERALFRSL,ALFRSL CRC 3 L S887L]LFRSLNLQAESVRGFNMGRAI NLQA STGSL PTPN1 c.6199G>A p.E206 YIQEDDIYDDSQEAEVIQSLLDVVD[p.E QSLLDVVDK,SLLDVVDKEA LUAD 3 7K 2067K]KEAQNLLNENNAAGYSCGPGT LKMNG PTPN1 c.2147_214 p.E716 QYHHKKTFSDATMLIHSSESEEEEE[p.E SESEEEEEA GBM 4 9de|AGG de| 716de|]APESVPQIPMLREKMEYSAQL QAALARI PTPN1 c.856G>A p.E286 THNKSTILVELINKEETALFHTDDI[p.E28 ALFHTDDIK,HTDDIKNAK,KNAKYISRL,HTDDIKNAKY,TALF MM 4 K 6K]KNAKYISRLFATRHKFYKQNKICTEQ HTDDIK,DIKNAKYISR,IKNAKYISRL,KNAKYISRLF PTPN1 c.1113_111 p.TG37 TYAVVQKRGAPAGAGSGTQTGTGTG[p. QTGTGTGAR UCS 8 8de|GACGG 8de| TG378de|]ARSAEEAPLYSKVTPRAQ G RPGAHAEDARGTL PTPN4 c.957de|T p.N319 NLWKACVEHHTFFRLDRPLPPQKNF[p. QKNFLHIIL,RPLPPQKNFL,LPPQKNFLHI STAD fs N319fs]LHIILH* PTPRB c.2178A>T p.Q726 SLTPGRLYTVTITTRSGKYENHSFS[p.Q7 HSFSHERTV,ENHSFSHER,FSHERTVPDK,GKYENHSFSH TGCT H 26H]HERTVPDKVQGVSVSNSARSDYL RVS PTPRB c.4678G>A p.D156 ENPNSNSKSFNIKLGAEMESLGGKC[p. KCNPTQQKF,GGKCNPTQQK,GKCNPTQQKF SKCM 0N D1560N]NPTQQKFCDGPLKPHTAYRIS IRAFT PTPRC c.2685A>C p.Q895 GLEAENKVDVYGYVVKLRRQRCLMV[p. RQRCLMVHV,LMVHVEAQY,MVHVEAQYI,VHVEAQYIL,L STAD H Q895H]HVEAQYILIHQALVEYNQFGET MVHVEAQY,RQRCLMVHVE,CLMVHVEAQY,MVHVEAQ EVNL YIL PTPRF c.3521G>A p.R117 PRWSTPEELELDELLEAIEQGGEEQ[p.R EQQRRRRQA,QQRRRRQAER PRAD 4Q 1174Q]QRRRRQAERLKPYVAAQLDVL PETFT PTPRJ c.1000G>T p.G334 HDESLVGPVDPSSGQQSRDTEVLLV[p. LVWLEPGT,RDTEVLLVW,VWLEPGTRY,VLLVWLEPGT, LUAD W G334W]WLEPGTRYNATVYSQAANGT WLEPGTRYNA,LVWLEPGTRY,RDTEVLLVWL EGQPQA PTPRT c.2783G>T p.R928 SWDTAKEDENRNKNRYGNIISYDHS[p. IISYDHSLV,NIISYDHSL,ISYDHSLVR,SYDHSLVRL,HSLVRLL LUAD L R928L]LVRLLVLDGDPHSDYINANYIDG VL,YDHSLVRLL,NIISYDHSLV,IISYDHSLVR,SYDHSLVRLL,IS YHR YDHSLVRL,YDHSLVRLLV PTPRT c.3224de|C p.P107 WPDHGVPCYATGLLGFVRQVKFLNP[p. RQVKFLNPR,QVKFLNPRK,VKFLNPRKL,RQVKFLNPRK STAD 5fs P1075fs]RKLGP* PTPR c.1675C>T p.P559 VNVPGPRRTISKLRNETYHVFSNLH[p.P NLHSGTTYL,LHSGTTYLF,SNLHSGTTY,FSNLHSGTTY,NLHS LUAD U S 559S]SGTTYLFSVRARTGKGFGQAALT GTTYLF,SGTTYLFSVR,HVFSNLHSGT,HSGTTYLFSV,SNLHS EIT GTTYL PTPR c.4300G>A p.D143 FFAAKTLRNYKPNMVETMDQYHFCY[p. CYNVALEYL,FCYNVALEY,DQYHFCYNV,YHFCYNVAL,QYH CRC U 4N D1434N]NVALEYLEGLESR* FCYNVAL,HFCYNVALEY,NVALEYLEGL,DQYHFCYNVA,MD QYHFCYNV PUF60 c.1187C>T p.S396 VMAAQAPGVITGVTPARPPIPVTIP[p.S VTIPLVGVV,PLVGVVNPI,PPIPVTIPL,RPPIPVTIPL,IPLVGV BLCA L 396L]LVGVVNPILASPPTLGLLEPKKEKE VNPI,PPIPVTIPLV,IPVTIPLVGV E PVRL4 c.1072G>A p.A358 LDPQEDSGKQVDLVSASVVVVGVIA[p. VIATLLFCL,ATLLFCLLV,TLLFCLLVV,VVVGVIATL,VGVIATL UCEC T A358T]TLLFCLLVVVVVLMSRYHRRKA LF,GVIATLLFCL,VIATLLFCLL,ATLLFCLLVV,TLLFCLLVVV,V QQMT VVGVIATLL,VVGVIATLLF PWW c.251de|C p.S84fs PVNDSHGRAPEEGDAEVMQLGSSSP[p. MQLGSSSPL,QLGSSSPLL,RTSCGCPSR,GVCPATATR,SSAP STAD P2B S84fs]LLPAGFSPPRPPAPSHPRPSCRR SACGR,GFSPPRPPA,LTRCGSGTR,SARGGVCPA,ATRGASS CPPEACPRTLPTSKAPPSLTRCGSGTRTS SA,CGRARCSVR,RARCSVRSA,TSCGCPSRR,APSHPRPSC,H CGCPSRRPGPSSARGGVCPATATRGAS PRPSCRRC,RPSCRRCPP,GPSSARGGV,CPATATRGA,LPAG SSAPSACGRARCSVRSARAR* FSPPR,VMQLGSSSPL,MQLGSSSPLL,TSKAPPSLTR,RTSCG CPSRR,SSSAPSACGR,AGFSPPRPPA,RTLPTSKAPP,GTRTS CGCPS,PSRRPGPSSA,RGASSSAPSA,RARCSVRSAR,SSSPLL PAGF,LLPAGFSPPR,RPSCRRCPPE,CPRTLPTSKA,LPTSKAP PSL,CPATATRGAS PXDN c.3935C>T p.T131 IPKVDLRVWQDCCADCRSRGQFRAV[p. RAVMQESQK,AVMQESQKK,SRGQFRAVM,RSRGQFRAV CRC L 2M T1312M]MQESQKKRSAQYSYPVDKD M,RAVMQESQKK,GQFRAVMQES MELSHLR PXDN c.4366C>A p.P145 CPPAPCPSPELVKGTCCPVCRDRGM[p. GMTSDSPEK,MTSDSPEKR,RGMTSDSPEK LUAD L 6T P1456T]TSDSPEKR* PYGO c.448de|C p.Q150 GPQPLRRQPPPFPPNPMGPAFNMPP[p. NMPPRVLAT,VLATHPQAT,RVLATHPQA,MPPRVLATH,AF STAD 2 fs Q150fs]RVLATHPQAT* NMPPRVLA,RVLATHPQAT,MGPAFNMPPR,GPAFNMPPR V PYHIN c.443G>C p.G148 NRLTAKGAEETLGPQKRKKPSEEET[p.G ATKRSKMSK,TATKRSKMSK LUSC 1 A 148A]ATKRSKMSKEQTRPSCSAGASTS TAM QRSL1 c.677C>T p.S226 AHCGLVGFKPSYGLVSRHGLIPLVN[p.S GLIPLVNLM,NLMDVPGIL,IPLVNLMDV,NLMDVPGILT,LV CRC L 226L]LMDVPGILTRCVDDAAIVLGALA NLMDVPGI GPD QSOX c.1202G>T p.R401 DDRKEGAVLAKKVNWIGCQGSEPHF[p. HFLGFPCSL,CQGSEPHFL,GSEPHFLGF,EPHFLGFPC,FLGFP LUAD 1 L R401L]LGFPCSLWVLFHFLTVQAARQ CSLWV,HFLGFPCSLW,QGSEPHFLGF,LGFPCSLWVL,SEPH NVDHS FLGFPC QSOX c.2048G>T p.R683 SLDMSLCVVLYVASSLFLMVMYFFF[p.R LMVMYFFFL,MVMYFFFLV,VMYFFFLVR,FLVRSRRWK,FFL LUAD 2 L 683L]LVRSRRWKVKHHHPAV* VRSRRW,LVRSRRWKV,YFFFLVRSR,FFFLVRSRR,FLMVMY FFFL,LMVMYFFFLV,FLVRSRRWKV,MVMYFFFLVR,FFFLV RSRRW,MYFFFLVRS,FFLVRSRRWK,LVRSRRWKVK,YFFF LVRSRR R3HD c.1763G>A p.S588 MPNQQQAAYQGMIGVQQPQNQGLL LLSNQRSSM,NQRSSMGGQM,GLLSNQRSSM CLL M2 N S[p.S588N]NQRSSMGGQMQGLVVQY TPLPSYQVP R3HD c.1774A>G p.S592 QQAAYQGMIGVQQPQNQGLLSSQRS[p. GMGGQMQGL,LLSSQRSGM,QRSGMGGQM,GMGGQM CLL M2 G S592G]GMGGQMQGLVVQYTPLPSY QGLV,SQRSGMGGQM,GLLSSQRSGM QVPVGSD R3HD c.616C>T p.R206 EFINDNNNQFKKFPQMTSYHRMLLH[p. RMLLHWVAA,MLLHWVAAY,SYHRMLLHW,HWVAAYFG CLL M2 W R206W]WVAAYFGMDHNVDQTGKA M,LLHWVAAYF,HRMLLHWVA,MLLHWVAAYF,RMLLHW VIINKTSN VAAY,SYHRMLLHWV,YHRMLLHWVA,TSYHRMLLHW,HR MLLHWVAA,LHWVAAYFGM RAB11 c.1787C>T p.S596 SLYEAKNLFAAQTKAQSLAAEIDTA[p.S ALRDELMEA,LAAEIDTAL,SLAAEIDTAL,ALRDELMEAL,LAA BLCA FIP4 L 596L]LRDELMEALKEQEEINFRLRQYM EIDTALR DKI RAB11 c.509G>A p.R170 WYKLHSKPGKKEKERGEIEVTIQFT[p.R IEVTIQFTH,IQFTHNNLS,THNNLSASM,HNNLSASMF,IQFT GBM FIP5 H 170H]HNNLSASMFDLSMKDKPRSPFS HNNLSA,FTHNNLSASM,VTIQFTHNNL,THNNLSASMF KIRD RAB13 c.500G>T p.R167 EHGIRFFETSAKSSMNVDEAFSSLA[p.R SLALDILLK,DEAFSSLAL,FSSLALDIL,SSLALDILLK,EAFSSLAL LUAD L 167L]LDILLKSGGRRSGNGNKPPSTDLK DI,VDEAFSSLAL TC RAB7L c.235C>T p.R79 YEIVRLQLWDIAGQERFTSMTRLYY[p.R RLYYWDASA,TSMTRLYYW,YYWDASACV,MTRLYYWDA, CRC 1 W 79W]WDASACVIMFDVTNATTFSNSQ WDASACVIM,SMTRLYYWDA,RLYYWDASAC,FTSMTRLYY RWKQ W,LYYWDASACV,YYWDASACVI,MTRLYYWDAS,YWDAS ACVIM,WDASACVIMF RAB8 c.58G>T p.G20 MAKTYDYLFKLLLIGDSGV[p.G20W]W LIGDSGVWK,GVWKTCVLF,VWKTCVLFR,LLIGDSGVW,W LUAD A W KTCVLFRFSEDAFNSTFISTIGIDF KTCVLFRF,GVWKTCVLFR,SGVWKTCVLF,VWKTCVLFRF,L LLIGDSGVW RABG c.2782_278 p.K928f LEEESAQLKEMCRRELDKAESEIKK[p.K9 SEIKKKQFY,IKKKQFYHW,AESEIKKKQF STAD AP1 3insA s 28fs]KQFYHW* RABG c.2782de|A p.K928f LEEESAQLKEMCRRELDKAESEIKK[p.K9 SLVTISRFV,KTVLSLVTI,VLSLVTISR,EIKKTVLSL,LSLVTISRF, STAD AP1 s 28fs]TVLSLVTISRFVLS* KKTVLSLVT,AESEIKKTV,SLVTISRFVL,TVLSLVTISR,EIKKTV LSLV,VLSLVTISRF,AESEIKKTVL,SEIKKTVLSL,KKTVLSLVTI RABG c.619A>G p.N207 PASADDFLPTLIYIVLKGNPPRLQS[p.N2 RLQSDIQYI,LQSDIQYIT,SDIQYITRF,QSDIQYITRF TGCT EF1 D 07D]DIQYITRFCNPSRLMTGEDGYYFT NL RAC1 c.101C>G p.P34R VGDGAVGKTCLLISYTTNAFPGEYI[p.P3 RTVFDNYSA,YIRTVFDNY,NAFPGEYIR,FPGEYIRTV,FPGEYI TGCT 4R]RTVFDNYSANVMVDGKPVNLGLW RTVF DTA RAC1 c.476C>T p.A159 LTPITYPQGLAMAKEIGAVKYLECS[p.A AVKYLECSV,SVLTQRGLK,KYLECSVLT,VKYLECSVL,VLTQR HNSC V 159V]VLTQRGLKTVFDEAIRAVLCPPPV GLKTV,CSVLTQRGLK,AVKYLECSVL KK RAC1 c.85C>T p.P29S IKCVVVGDGAVGKTCLLISYTTNAF[p.P TTNAFSGEY,FSGEYIPTV,SGEYIPTVF,YTTNAFSGEY,TTNA SKCM 29S]SGEYIPTVFDNYSANVMVDGKPV FSGEYI,FSGEYIPTVF NLG RAD5 c.205G>T p.D69Y TIIECLKYICTGDFPPGTKGNTFVH[p.D6 GNTFVHYPK,NTFVHYPKV,KGNTFVHY,KGNTFVHYPK,G LUAD 0 9Y]YPKVAQETDVRAQIRLQFRDVNGELI TKGNTFVHY,NTFVHYPKVA,YPKVAQETDV RAD5 c.946de|A p.T316f RDFTNIYWSQNRPDVKKQKLQNDKK[p. KQKLQNDKKL STAD 1AP2 s T316fs]L* RAD5 c.499G>A p.D167 VQIPECFGGVAGEAVFIDTEGSFMV[p. FMVNRVVDL,MVNRVVDLA,EGSFMVNRV,FMVNRVVDL BLCA 1C N D167N]NRVVDLATACIQHLQLIAEKHK A,SFMVNRVVDL,DTEGSFMVNR,TEGSFMVNRV GEEH RAD5 c.670T>C p.Y224 FTLDNILSHIYYFRCRDYTELLAQV[p.Y2 ELLAQVHLL,AQVHLLPDF,TELLAQVHL,AQVHLLPDFL,LAQ BLCA 1C H 24H]HLLPDFLSEHSKVRLVIVDGIAFPFR VHLLPDF,HLLPDFLSEH,TELLAQVHLL RAF1 c.770C>T p.S257 YSTPHAFTFNTSSPSSEGSLSQRQR[p.S RQRLTSTPN,LTSTPNVHM,SQRQRLTST,RLTSTPNVH,LTST CRC L 257L]LTSTPNVHMVSTTLPVDSRMIED PNVHMV,RQRLTSTPNV,RLTSTPNVHM,SQRQRLTSTP AIR RALG c.1192C>T p.R398 LTEREPSSSSLCSIDEEHLTDIEIV[p.R398 IVCRVFSSK,LTDIEIVCRV,EIVCRVFSSK,IVCRVFSSKR,HLTDI CRC APA1 C C]CRVFSSKRSNVNFVTEIFRQAFLLPI EIVCR,TDIEIVCRVF,IEIVCRVFSS RALG c.1136de|C p.T379f RSDSAPPTPVNRLSMPQSAAVSTTP[p. TTPHITGGT,SAAVSTTPH,AAVSTTPHI,TPHITGGTGL,SAAV STAD APB s T379fs]HITGGTGLLL* STTPHI RALG c.1142G>A p.R381 SKSATFPSEKARHLLDDSVLESRSP[p.R3 RSPQRGLAL,SVLESRSPQR,LESRSPQRGL,SRSPQRGLAL BLCA PS1 Q 81Q]QRGLALTSSSAVTNGLSLGSSESSE F RANB c.2700G>T p.M90 HSDLLQYRKLSQSYYPLLECLTQDH[p.M LTQDHISFI,CLTQDHISF,TQDHISFII,CLTQDHISFI,LLECLTQ TGCT P17 0I 900I]ISFIINLEPPVLMYVLTSISEGLTTL DHI,LTQDHISFII,QDFIISFIINL RANB c.3691C>T p.R123 VESKEWKERGIGNVKILRHKTSGKI[p.R KTSGKICLL,CLMRREQV,SGKICLLMR,HKTSGKICL,TSGKIC CRC P2 1C 1231C]CLLMRREQVLKICANHYISPDM LLMR,KTSGKICLLM,SGKICLLMR,CLLMRREQVL,RHKTSG KLTP KICL,HKTSGKICLL RANB c.1157T>G p.L386 EATPEKESLAESAAAYTKATARKCL[p.L3 CLWEKVEVI,TARKCLWEK,KATARKCLW,ATARKCLWEK KIRC P3 W 86W]WEKVEVITGEEAESNVLQMQCKL FVF RANB c.2743C>T p.R915 QWGLCIFDDIIEHCSPTSFKYVEYF[p.R9 YVEYFWWPM,SFKYVEYFW,KYVEYFWWP,EYFWWPMLL, CESC P6 W 15W]WWPMLLNMRDNNPEVRQAAA FWWPMLLNM,FKYVEYFWW,VEYFWWPML,YVEYFWW YGLGVM PML,SFKYVEYFWW,KYVEYFWWPM,VEYFWWPMLL,YF WWPMLLNM,FWWPMLLNMR,TSFKYVEYFW RANB c.2950A>C p.I984L LVKVIKCANSKTKKNVIATENCISA[p.I98 ISALGKILK,ALGKILKFK,SALGKILKF,TENCISALG,CISALGKIL LUSC P6 4L]LGKILKFKPNCVNVDEVLPHWLSWL K,SALGKILKFK,IATENCISAL,ISALGKILKF P RAPG c.1067G>T p.R356 LPGKFKNLFRKFENLTDPCRNHKSY[p.R KSYLEVISK,SYLEVISKM,RNHKSYLEV,KSYLEVISKM,SYLEVI LUAD EFL1 L 356L]LEVISKMKPPVIPFVPLILKDLTFLH SKMK,RNHKSYLEVI RARS2 c.16C>T p.R6C MACGF[p.R6C]CRAIACQLSRVLNLPPE MACGFCRAI BLCA NLITSISAV RASAL c.245G>A p.R82H VSTQPAPRSIFRRVLSAPPKESRTS[p.R8 RTSHLRLSK,TSHLRLSKA,SHLRLSKAL,HLRLSKALW,RTSHL GBM 3 2H]HLRLSKALWGRHKNPPPEPDPEPE RLSKA,HLRLSKALWG,KESRTSHLRL,SHLRLSKALW QE RASG c.562G>A p.A188 LAALRQGPEGLVGADKPISYRTKPP[p.A SYRTKPPTS,RTKPPTSIH,YRTKPPTSI,SYRTKPPTSI,RTKPPT KIRC EF1C T 188T]TSIHRELLGVCSDPYTLAQQLTHV SIHR,TSIHRELLGV,KPPTSIHREL EL RASIP c.1801C>T p.R601 ATLLALCVQHSARELELGHLPRLLG[p.R RLLGCLARL,HLPRLLGCL,LLGCLARLI,CLARLIKEA,LPRLLGC ACC 1 C 601C]CLARLIKEAVWEKIKEIGDRQPEN LA,RLLGCLARLI,CLARLIKEAV,HLPRLLGCLA,LLGCLARLIK HP RB1 c.948_951d p.N316 FKNFIPFMNSLGLVTSNGLPEVENL[p.N KKFILKIKI,DTKKFILKIK,VENLNDTKKF GBM e|TCTT fs 316fs]NDTKKFILKIKI* RBBP4 c.988G>A p.E330 NLKLKLHSFESHKDEIFQVQWSPHN[p. QVQWSPHNK,SPHNKTILA,VQWSPHNKT,FQVQWSPHNK, LAML K E330K]KTILASSGTDRRLNVWDLSKIGE SPHNKTILAS,VQWSPHNKTI EQS RBBP7 c.820G>A p.E274 QKLMIWDTRSNTTSKPSHLVDAHTA[p. LVDAHTAKV,HLVDAHTAK,HTAKVNCLS,TAKVNCLSF,HLV CRC K E274K]KVNCLSFNPYSEFILATGSADKT DAHTAKV,KVNCLSFNPY,HTAKVNCLSF VAL RBBP7 c.937G>A p.E313 LATGSADKTVALWDLRNLKLKLHTF[p.E KLHTFKSHK,KLKLHTFKS,LKLHTFKSH,FKSHKDEIF,NLKLKL CRC K 313K]KSHKDEIFQVHWSPHNETILASS HTFK,KLKLHTFKSH,KSHKDEIFQV,HTFKSHKDEI GTD RBFOX2 c.1018G>A p.A340T NTYIPLISLPLVPGFPYPTAATTAA[p.A3 ATFRGAHLR,AATTAATFR,TTAATFRGA,TAATTAATF,TAATT CRC 40T]TFRGAHLRGRGRTVYGAVRAVPPTAI AATFR,TFRGAHLRGR,AATFRGAHLR,YPTAATTAAT,PTAATTAATF RBL2 c.379G>A p.E127K VSKGTVEGNYVSLTRILKCSEQSLI[p.E1 SLIKFFNKM,QSLIKFFNK,LIKFFNKMK,KFFNKMKKW,CSEQ UCEC 27K]KFFNKMKKWEDMANLPPHFRERTERL SLIKF,SEQSLIKFF,SLIKFFNKMK,LIKFFNKMKK,EQSLIKFFN K,KCSEQSLIKF,IKFFNKMKKW RBM1 c.856_876d p.AAAA LTSTSLDPYDRHLLPTSGAAATAAA[p.A GAAATAAAV,ATAAAVTAA,TAAAVTAAS,SGAAATAAAV, PAAD 4 e|GCTGCTG AAA286de| AAAAAA286de|]VTAASTSYYGRDRSPL TAAAVTAAST CTGCAGCA RRATAPVPTVGEGYGYGHESELSQASAAAR GCAGCC RBM1 c.1168G>T p.G390W FREKNVPTTKGAPKNTTKSWQGRIL[p. KSWQGRILW,WENEEEEDL,TKSWQGRILW LUAD 9 G390W]WENEEEEDLAESGRLFVRNLPYTSTE RBM2 c.1930C>G p.P644A TTSPKPLVQQPILPVVKQSVKERLG[p.P SVKERLGAV,KERLGAVPS,LGAVPSSTI,RLGAVPSSTI, BLCA 6 644A]AVPSSTIEPAEAQSASSDLPQNVTKL KERLGAVPSS RBM39 c.1058C>T p.T353I ERTDASSASSFLDSDELERTGIDLG[p.T3 LGITGRLQL,ITGRLQLMAR,LERTGIDLGI,LGITGRLQLM UCEC 53I]ITGRLQLMARLAEGTGLQIPPAAQQA RBM47 c.1485_150 p.495_ HTVEHMISPIAVQPDPASAAAAAAA[p.495_5 ASAAAAAAAV,SAAAAAAAVI PAAD 5de|GGCCG 502AA 02AAAAAAAA>A]VIPTVSTPPPF CAGCCGCC AAAAAA>A QGRPITPVYTVAPNVQRIPTAGIYGASYVPFAAPA GCAGCCGC RBM6 c.2024T>G p.V675G RQDGESKTIMLKRIYRSTPPEVIVE[p.V6 VIVEGLEPY,VIVEGLEPYV,EVIVEGLEPY MM 75G]GLEPYVRLTTANVRIIKNRTGPMGHT RBM6 c.287_288 p.R96fs SYGARDGPHGDYRGGEGPGHDFRGG[p. FRGGRFFVF,HDFRGGRFF,DFRGGRFFVF,HDFRGGRFFV STAD insG R96fs]RFFVF* RCL1 c.335C>A p.P112Q HDCSVLRGIGYYLESLLCLAPFMKH[p.P FMKHQLKIV,QLKIVLRGV,PFMKHQLKI,APFMKHQLK,MK LUAD 112Q]QLKIVLRGVTNDQVDPSVDVLKATAL HQLKIVL,CLAPFMKHQL,HQLKIVLRGV,FMKHQLKIVL,LAP FMKHQLK,APFMKHQLKI RDH8 c.593C>T p.A198V LLQFNIFISLVEPGPVVTEFEGKLL[p.A19 KLLVQVSMA,LVQVSMAEF,TEFEGKLLV,GKLLVQVSM,FE GBM 8V]VQVSMAEFPGTDPETLHYFRDLYLPA GKLLVQV,VTEFEGKLLV,LLVQVSMAEF,VQVSMAEFPG,TE FEGKLLVQ,FEGKLLVQVS REG1B c.170G>T p.W57L PRISCPEGTNAYRSYCYYFNEDPET[p.W ETLVDADLY,YFNEDPETL,YYFNEDPETL LUAD 57L]LVDADLYCQNMNSGNLVSVLTQAEGA REG1B c.201G>T p.M67I AYRSYCYYFNEDPETWVDADLYCQN[p. CQNINSGNL,NINSGNLVSV,CQNINSGNLV,INSGNLVSVL LUSC M67I]INSGNLVSVLTQAEGAFVASLIKESS REG3A c.449C>T p.S150L SDVMNYFAWERNPSTISSPGHCASL[p. SLLRSTAFL,LLRSTAFLR,SPGHCASLL,ASLLRSTAF,LRSTAFL LUAD S150L]LRSTAFLRWKDYNCNVRLPYVCKFTD RW,SLLRSTAFLR,ASLLRSTAFL,CASLLRSTAF,LLRSTAFLRW REG4 c.329G>T p.G110V GYQRSQPIWIGLFIDPQKRQQWQWID[p. WIDVAMYLY,QWIDVAMYL,WQWIDVAMY,RQQWQWID LUAD G110V]VAMYLYRSWSGKSMGGNKHCAEMSSN V,QQWQWIDVA,QWQWIDVAM,VAMYLYRSW,WQWID VAMYL,WIDVAMYLYR,QWQWIDVAMY,QWIDVAMYLY,QQW QWIDVAM,RQQWQWIDVA REN c.45_47 p.15_16 MDGWRRMPRWGLLLL[p.15_16LL>L] MPRWGLLLLW GBM de|GCT LL>L WGSCTFGLPTDTTTFKRIFLKRMPSIRE RERE c.528G>C p.K176N PACSLPVASQPPQHLSEAGRGPVGS[p. GSNRDHLLM,AGRGPVGSNR,GPVGSNRDHL BLCA K176N]NRDHLLMNVKWYYRQSEVPDSVYQHL REV3L c.88G>T p.A30S RIVTADYYMASPLQGLDTCQSPLTQ[p. SPVKKVPVV,CQSPLTQSP,CQSPLTQSPV,TQSPVKKVPV TGCT A30S]SPVKKVPVVRVFGATPAGQKTCLHLH RFC3 c.245T>A p.I82N RELYGVGVEKLRIEHQTITTPSKKK[p.I82 TPSKKKNEI,KKKNEISTI,KKNEISTIA,NEISTIASNY, TGCT N]NEISTIASNYHLEVNPSDAGNSDRVV SKKKNEISTI RFC3 c.888G>T p.K296N LLEVRGRLYELLTHCIPPEIIMKAC[p.K29 IMKACNEESR,NEESRSCDIF TGCT 6N]NEESRSCDIF* RGMB c.187A>C p.S63R AWTGMGLRAAPSSAAAAAAEVEQRR[p.S63R] RPGLCPPPL,VEQRRRPGL,RRPGLCPPPL ACC RPGLCPPPLELLLLLLFSLGLLHAGD RGS6 c.1097G>T p.W366L LKDQVGRDQFLRFLESEFSSENLRF[p. FLLAVQDLK,LLAVQDLKK,RFLLAVQDL,FSSENLRFL,SENLR LUSC W366L]LLAVQDLKKQPLQDVA FLLA,FLLAVQDLKK,RFLLAVQDLK,FSSENLRFLL,SENLRFLL KRVEEIWQEF AV,LRFLLAVQDL RGS7 c.130C>T p.R44C PNMLVYRKMEDVIARMQDEKNGIPI[p. CTVKSFLSK,IPICTVKSF,KNGIPICTVK,CTVKSFLSKI,IPICTVKSFL SKCM R44C]CTVKSFLSKIPSVFSGSDIVQWLIKN RGS9BP c.286G>T p.A96S ERAEFERLWVAFSGCLDLLEADMRR[p. RSLELGAAF,LEADMRRSL,ADMRRSLEL,SLELGAAFPL,RRSLELGAAF ACC A96S]SLELGAAFPLHAPRRPLVRTGVAGAS RGSL1 c.664G>A p.V222I HTKMTMAKEEACHGLMQEYETRLYS[p.V RLYSICYTH,EYETRLYSI,LYSICYTHI,ETRLYSICY,YETRLYSIC, BRCA 222I]ICYTHIGGLPLNMSIKKCHHFQKRYS RLYSICYTFHI,SICYTHIGGL,QEYETRLYSI,YETRLYSICY RHBDD3 c.101_102 p.G34fs SPALPLASSVLMLLMSTLWLVGAGP[p. AVAGPLAGA,GLAAGVPPG,EIPACLSPA,SAAGRPWAV,CS KICH insG G34fs]RPGPGPGAVAGPLAGAPAADP RQLWIHA,WAAGSAAGR,RPWAVQCSR,GPRPGPGPG,RP CPGPHGPARPAPEPAAPAHCGLAAGV GPGPGAV,GPGAVAGPL,GPLAGAPAA,GPHGPARPA,APA PPGHAEIPACLSPARPGFWAAGSAAGR HCGLAA,SPARPGFWA,CLSPARPGF,AEIPACLSP,GFWAA PWAVQCSRQLWIHACPPGHAGWGGTPP* GSAA,AGSAAGRPW,WAVQCSRQL,VQCSRQLWI,RQLWIHACP,WIH ACPPGHA,TLWLVGAGPR,EIPACLSPAR,FWAAGSAA GR,EPAAPAHCGL,GPRPGPGPGA,RPGPGPGAVA,GPARPAPE PA,RPAPEPAAPA,SPARPGFWAA,RPGFWAAGS A,AEIPACLSPA,ACLSPARPGF,AAGSAAGRPW,WAVQCSRQLW, RQLWIHACPP,HACPPGHAGW RHEB c.103T>A p.Y35N AILGYRSVGKSSLTIQFVEGQFVDS[p.Y3 FVDSNDPTI,GQFVDSNDPT,SNDPTIENTF KIRC 5N]NDPTIENTFTKLITVNGQEYHLQLVD RHOA c.118G>C p.E40Q ACGKTCLLIVFSKDQFPEVYVPTVF[p.E4 VFQNYVADI,YVPTVFQNY,VPTVFQNYV,YVPTVFQNYV,F HNSC 0Q]QNYVADIEVDGKQVELALWDTAGQED QNYVADIEV,VYVPTVFQNY,TVFQNYVADI,VPTVFQNYVA RHOA c.125A>G p.Y42C GKTCLLIVFSKDQFPEVYVPTVFEN[p.Y4 VPTVFENCV,YVPTVFENCV,TVFENCVADI,CVADIEVDGK, STAD 2C]CVADIEVDGKQVELALWDTAGQEDYD VYVPTVFENC,FENCVADIEV RHOBTB1 c.1391C>T p.T464M VLEMFDLRMMVENIMNKEAFMNQEI[p. FMNQEIMKA,IMKAFHVRK,AFMNQEIMK,EIMKAFHVR, CRC T464M]MKAFHVRKANRIKECLSKGTFSDVTF MNQEIMKAF,MKAFHVRKA,EAFMNQEIM,QEIMKQFHV, FMNQEIMKAF,IMKAFHVRKA,EAFMNQEIMK,EIMKAFHVRK, KEAFMNQEIM RHPN2 c.217G>A p.V73M LKAVRMRTGAENLLKVATNSKVREQ[p. QMRLELSFV,KVREQMRLE,NSKVREQMR,EQMRLELSF,SK TGCT V73M]MRLELSFVNSDLQMLKEELEGLNISV VREQMRL,VREQMRLEL,REQMRLELS,EQMRLELSFV,KVR EQMRLEL,REQMRLELSF RILPL1 c.1074C>A p.S358R RIPQPPPIAHPRTSPQPESGIKRLF[p. SGIKRLFRF,GIKRLFRFF,KRLFRFFSR,LFRFFSRDK,ESGIKRLF KICH S358R]RFFSRDKKRLANTQRNVHIQ R,RFFSRDKKR,RLFRFFSRDK,SGIKRLFRFF,GIKRLFRFFS,IK ESFGQW RLFRFFSR,LFRFFSRDKK RIMBP2 c.2489G>A p.R830H FPRGSAGPQRSRPVTVPSIDDYGRD[p. RDHLSPDFY,YGRDHLSPDF GBM R830H]HLSPDFYEESETDPGAEELPARIFVA RIMBP3 c.1187_1189 p.A396de| HELIKLNWLLAKALWVLARRCYTLQ[p.A396 RCYTLQENK,TLQENKQLR,QENKQLRRA,YTLQENKQLR KIRC de|CGG de|]ENKQLRRAGCPYQADEKVKRLKVKRAEL RIMBP3 c.3461A>G p.Q1154R YADGLKVCEVADATAGSTLLEFSQL[p.Q115 LLEFSQLRV,TLLEFSQLR,SQLRVPLTW,LEFSQLRVP,TLLEFSQLRV, TGCT 4R]RVPLTWQKVSVRTMSLCGESLDSVPA QLRVPLTWQK,STLLEFSQLR,FSQLRVPLTW,LEFSQLRVPL RIMS2 c.1203de|A p.V401fs LGLKVVGGKMTESGRLCAFITKVKK[p.V FITKVKKEV STAD 401fs]EV* RIMS2 c.164G>T p.R55L EREEYSQYATSDTAMPRSPSDYADR[p. LSQHEPQFY,SPSDYADRL,RLSQHEPQF,RLSQHEPQFY LUAD R55L]LSQHEPQFYEDSDHLSYRDSNRRSHR RIMS2 c.1796G>A p.R599Q KRRTKTVKKTLEPKWNQTFIYSPVH[p.R FIYSPVHQR,HQREFRERM,IYSPVHQREF,TFIYSPVHQR,YS CRC 599Q]QREFRERMLEITLWDQARVREEESEF PVHQREFR,HQREFRERML RIN3 c.1345C>G p.L449V DTPRESTEQGQDTEVKASDPHSMPE[p.L44 SMPEVPRTA,SMPEVPRTAK,HSMPEVPRTA,VPRTAKQPPV KIRC 9V]VPRTAKQPPVPPPRKKRISRQLASTL RIN3 c.2123C>T p.S708L LYKCVLKPLKEAINSCLHQIHSKDG[p.S7 HQIHSKDGL,SKDGLLQQL,HQIHSKDGLL CRC 08L]LLQQLKENQLVILATTTTDLGVTTSV RING1 c.511de|G p.G171fs QAMHRAQRVRRPIPGSDQTTTMSGG[p. QTTTMSGGK,GGKESPGREK,KESPGREKGM STAD G171fs]KESPGREKGMEKM* RINL c.1205C>T p.P402L RRRQTALRAGAGPPGAQGPGPEGQS[p. SLAPALRSR,GPGPEGQSL,PEGQSLAPA,SLAPALRSRI,EGQ ACC P402L]LAPALRSRIHERLAHLHAACAPRRKV SLAPALR,PEGQSLAPAL RINT1 c.321de|A p.L107fs SKMQLEEQVLTISSEIPKRIRSALK[p.L10 MQKNQSNFL,KLISSAPLT,FLISFWSRK,KMQKNQSNF,RIRS STAD 7fs]MQKNQSNFLISFWSRKLISSAPLTAIC* ALKMQ,ISFWSRKLI,WSRKLISSA,NFLISFWSR,NQSNFLISF, KRIRSALKM,QKNQSNFLI,RKLISSAPL,ISSAPLTAI,KMQKN QSNFL,FLISFWSRKL,KLISSAPLTA,LISSAPLTAI,MQKNQSNFLI, RIRSALKMQK,SNFLISFWSR,KNQSNFLISF,NFLISFWSRK,SRKLI SSAPL,LKMQKNQSNF,NQSNFLISFW RIT1 c.270G>T p.M90I DDEPANLDILDTAGQAEFTAMRDQY[p. FTAMRDQYI,AMRDQYIRA,YIRAGEGFI,QYIRAGEGF,TAM LUAD M90I]IRAGEGFIICYSITDRRSFHEVREFK RDQYIR,IRAGEGFII,YIRAGEGFII,QYIRAGEGFI,AMRDQYI RAG,FTAMRDQYIR,DQYIRAGEGF RIT2 c.254G>T p.R85L QVRIDNEPAYLDILDTAGQAEFTAM[p. GQAEFTAML,TAMLEQYMR,FTAMLEQYM,AEFTAMLEQ,FTAM LUAD R85L]LEQYMRGGEGFIICYSVTDRQSFQEA LEQYMR,AEFTAMLEQY RLBP1 c.215C>T p.A72V KAKDELNEREETREEAVRELQEMVQ[p. RELQEMVQV,QEMVQVQAA,VQAASGEEL,LQEMVQVQAA,VQAA CRC A72V]VQAASGEELAVAVAERVQEKDSGFFL SGEELA,QEMVQVQAAS RLBP1 c.841G>A p.D281N PFLKSKLLERVFVHGDDLSGFYQEI[p.D2 FYQEINENI,YQEINENIL,NENILPSDF,GFYQEINENI,FYQEI CRC 81N]NENILPSDFGGTLPKYDGKAVAEQLF NENIL,QEINENILPS RLIM c.1502C>T p.S501L SPSSSSGGESSETSSDLFEGSNEGS[p.S5 SLSSGSSGA,FEGSNEGSL KIRC 01L]LSSGSSGARREGRHRAPVTFDESGSL RLN2 c.412A>T p.S138C QQHVPVLKDSSLLFEEFKKLIRNRQ[p.S LIRNRQCEA,RQCEAADSS,CEAADSSPS,KLIRNRQCEA,LIRN LUAD 138C]CEAADSSPSELKYLGLDTHSRKKRQL RQCEAA,RQCEAADSSP RNAS c.380C>T p.A127V HSFPNRSRFWKHEWEKHGTCAAQVD[p. QVDVLNSQK,VLNSQKKYF,AQVDVLNSQK,QVDVLNSQKK CRC ET2 A127V]VLNSQKKYFGRSLELYRELDLNSVLL RNF11 c.2313de|C p.R771fs HEVMQRMEVQRRRMMQHPTRAHERP[p. TMVMGIIFM,VMGIIFMCL,HIGCQTMV,RLCPHILDR,QT STAD 1 R771fs]HPIHIGCTQTMVMGIIFM MVMGIIF,RGLPGNWEL,RAHERPHPI,MGIIFMCLR,CTQT CLRLCPHILDRLQRGLPGNWELKLE* MVMGI,MVMGIIFMC,CRLCPHIL,HERPHPIHI,IHIGCTQT M,IGCTQTMVM,FMCLRLCPH,LQRGLPGNW,LPGNWELK, MVMGIIFMCL,FMCLRLCPH,RLCPHILDR,VMGIIFMCLR, RGLPGNWELK,RAHERPHPIH,QTMVMGIIFM,RPHPIHI GCT,HIGCTQTMVM,TQTMVMGIIF,RLQRGLPGNW RNF11 c.515C>T p.A172V YRGIHSYLRYLKPKDTSMGNSSSGM[p.A172 NSSSGMVRK,SMGNSSSGMV CRC 3B V]VRKGPIRAPGHLRATVRWDYQPDICK RNF14 c.25A>G p.S9G MAWRRREA[p.S9G]GVGARGVLALAL AWRRREAGV,MAWRRREAG,RRREAGVGAR,MAWRRRE ACC 9 LALALCVPGARGRA AGV,REAGVGARGV RNF15 c.623C>T p.S208L LERNITVTMYITIGTRNLQKYVSRT[p.S2 RTLVVFVSI,KYVSRTLVV,YVSRTLVVF,VSRTLVVFV,LQKYVS CRC 0 08L]LVVFVSISFIVLMIISLAWLVFYYIQ RTL,LVVFVSISF,QKYVSRTLV,YVSRTLVVFV,NLQKYVSRTL, LQKYVSRTLV,LVVFVSISFI,KYVSRTLVVF,RTLVVFVSIS,TLV VFVSISF,QKYVSRTLVV RNF150 c.707G>A p.R236Q FVSISFIVLMIISLAWLVFYYIQRF[p.R23 FYYIQRFQY,YYIQRFQYA,IQRFQYANA,YIQRFQYANA,FYYI CRC 6Q]QYANARDRNQRRLGDAAKKAISKLQI QRFQYA,YYIQRFQYAN,IQRFQYANAR,VFYYIQRFQY,FQY ANARDRN RNF15 c.283C>T p.P95S PDDPEVLAVIAIPHTSEHTPVFIKL[p.P9 KLSSNGCYM,IKLSSNGCY,LSSNGCYML,KLSSNGCYML,FIK SKCM 2 5S]SSNGCYMLPLPISKERALLPGDMGCR LSSNGCY,IKLSSNGCYM,SSNGCYMLPL RNF17 c.1052C>G p.S351C KKYNNKKELSCYDTYPPLEKKKVDM[p.S KKKVDMCVL KIRC 351C]CVLTSEAPPPPLQPETNDVHLEAKNF RNF22 c.397G>A p.A133T PLAASSPAWRPPPGQARPPGSPGQS[p. SPGQSTQLPL,GQSTQLPLDL,TQLPLDLLPS ACC 2 A133T]TQLPLDLLPSLPRESQIFVISRHGMP RNF39 c.787G>T p.G263C HRRLLISADRRSVQLAPPGTPAPPD[p.G GTPAPPDCPK ACC 263C]CPKRFDQLPAVLGAQGFGAGRHCWEV RNF43 c.1976de|G p.G659fs PSTSSLFNLQKSSLSARFIPQRKRRG[p.G RMQLCTQLA,TQLARFFPI,RFFPITPPV,FFPITPPVW,ITPPV STAD 659fs]VPPSPPLALGPRMQLCTQLARFF WHIL,RGVPPSPPL,MQLCTQLAR,HPQRKRRGV,VPPSPPL PITPPVWHILGPQRHTP* AL,RKRRGVPPS,LALGPRMQL,QLCTQLARF,FPITPPVWFI, RMQLCTQLAR,MQLCTQLARF,CTQLARFFPI,RFFPITPPVW, RGVPPSPPLA,FPITPPVWHI,SPPLALGPRM,GPRMQLCTQ L,RRGVPPSPPL,QLCTQLARFF,TQLARFFPIT,ARFFPITPPV RNF43 c.348_349 p.P116fs NASDDDNLEPGFISIVKLESPRRAP[p.P116fs] SPRRAPPPL,RRAPPPLPV STAD insC PPLPVTG* RNF43 c.647C>T p.S216L PPAWPDYDVWILMTVVGTIFVIILA[p.S IILALVLRI,IFVIILALV,VIIIALVLR,TIFVIILAL,FVIILA CRC 216L]LVLRIRCRPRFISRPDPLQQRTAWAIS LVL,TIFVIILALV,VIILALVLRI,IFVIILALVL,LVLRIRCRPR, FVIILALVLR,IILALVLRIR,LALVLRIRCR,GTIFVIILAL RNMT c.1174de|A p.K392fs PEFLVYFPLLNEMAKKYNMKLVYKK[p. VYKKHFWNS,KKHFWNST,KHFWNSTK,STKKRLRTM,K STAD K392fs]HFWNSTKKRLRTMKIKCS* KRLRTMKI,RLRTMKIKC,HFWNSTKKR,MKLVYKKHF,YKKH FWNST,STKKRLRTMK,KKHFWNSTKK,KKRLRTMKIK,RLRT MKIKCS,FWNSTKKRLR,NMKLVYKKHF,MKLVYKKHFW RNPC3 c.347de|A p.E116fs LVVEFAKEQDRVHSPCPTSGSEKKK[p.E GLMTLSKMI,LMTLSKMIK,MTLSKMIKK,TLSKMIKKK,LSK CESC 116fs]GLMTLSKMIKKKKNLVI* MIKKKK,MIKKKKNLV,KGLMTLSKM,IKKKKNLVI,KMIKKKK NLV,GLMTLSKMIK,LMTLSKMIKK,MTLSKMIKKK,TLSKMI KKKK,KKKGLMTLSK,MIKKKKNLVI,SKMIKKKKNL,SEKKKG LMTL,KKGLMTLSKM ROBO2 c.3052G>A p.D1018N SQITQATPYATTQILHSNSIHELAV[p.D1 SIHELAVNL,HELAVNLPD,AVNLPDPQWK,NSIHELAVNL,L UCEC 018N]NLPDPQWKSSIQQKTDLMGFGYSLPD AVNLPDPQW,HELAVNLPDP ROBO2 c.3238_323 p.P1080fs KNKNSSKPQKNNGSTWANVPLPPPP[p. TLCSGTTRK,GTLCSGTTR,SPAPSWHGA,APSWHGAGT,GT STAD 9insC P1080fs]SPAPSWHGAGTLCSGTTRKWL* LCSGTTRK,VPLPPPPSPA,SPAPSWHGAG,APSWHGAGTL ROBO2 c.3877de|A p.K1293fs PTSPFSTDSNTSAALSQSQRPRPTK[p.K WTNNQHCLI,REGGWTNNQH STAD 1293fs]NTREGGWTNNQHCLIEGKE* ROCK1 c.1552A>T p.T518S HRINEYQRKAEQENEKRRNVENEVS[p. EVSSLKDQL,NVENEVSSLK,RNVENEVSSL,NEVSSLKDQL PRAD T518S]SLKDQLEDLKKVSQNSQLANEKLSQL ROR2 c.2014G>A p.D672N KLLGNSLLPIRWMAPEAIMYGKFSI[p.D6 NSDIWSYGV,KFSINSDIW,SINSDIWSY,IMYGKFSIN,GKFSI CRC 72N]NSDIWSYGVVLWEVFSYGLQPYCGYS NSDI,FSINSDIWSY,NSDIWSYGVV,IMYGKFSINS,INSDIWS YGV,GKFSINSDIW RORB c.280G>T p.G94W NRNRCQHCRLQKCLALGMSRDAVKF[p. AVKFWRMSK,MSRDAVKFW,AVKFWRMSKK,MSRDAVKF LUAD G94W]WRMSKKQRDSLYAEVQKHQQRLQEQR WR,DAVKFWRMSK,GMSRDAVKFW ROS1 c.734G>T P.R245I FPGGPILGYNLRLISKNQKLDAGTQ[p.R GTQITSFQF,TQITSFQFY,QKLDAGTQI,GTQITSFQFY,ITS UCEC 245I]ITSFQFYSTLPNTIYRFSIAAVNEVG FQFYSTL,NQKLDAGTQI,LDAGTQITSF,AGTQITSFQF RP1 c.5312C>T p.S1771L WLLKENHLLRMSSENPGMCGNADTT[p. DTTLVDTLL,GMCGNADTTL LUSC S1771L]LVDTLLDNNSSEVPYSHFGNLAPGPT RPA1 c.92G>A p.R31H SEGAIAAIMQKGDTNIKPILQVINI[p.R3 LQVINIHPL,ILQVINIHPIL,LQVINIHPIT HNSC 1H]HPITTGNSPPRYRLLMSDGLNTLSSF RPL10L c.560A>C p.K187T RQKIHISKKWGFTKFNADEFEDMVA[p. DEFEDMVAT,DEFEDMVATK,FEDMVATKCL LUAD K187T]TKCLIPDGCGVKYVPSHGPLDKWRVL RPL13 c.319G>C p.G107R QTMRGMPPHKTKPGQAALDCLKVFD[P.G107R] VFDRIPPPY,RIPPPYDKK,KVFDRIPPP,KVFDRIPPPY, UCS AP20 RIPPPYDKKKRMVVPAALKVVRLKPA RIPPPYDKKK RPL19 c.451C>T p.R151C KVKGNVFKNKRILMEHIHKLKADKA[p. KLKADKACK,KLKADKACKK TGCT R151C]CKKLLADQAEARRSKTKEARKRREER RPL22 c.44de|A p.K15fs MAPVKKLVVKGGKK[p.K15fs]RSKF* VVKGGKKRSK,VKGGKKRSKF UCEC RPL5 c.172_173 p.R58fs KRLVIQDKNKYNTPKYRMIVRVTNR[p. HLSDCLCPY,RSVCTRTAK,MIVRVTNRY,IVRVTNRYH,RVTN TGCT de|AG R58fs]YHLSDCLCPYRGGYDSLRSVCTR RYHLS,RTAKIWCEG,CLCPYRGGY,DSLRSVCTR,VRVTNRY TAKIWCEGWPDKLCCSILYWPAAGPQASQ* HL,KLCCSILYW,CSILYWPAA,DKLCCSILY,WPAAGPQAS,W PDKLCCSI,SLRSVCTRTA,RMIVRVTNRY,KIWCEGWPDK,H LSDCLCPYR,IWCEGWPDKL,IVRVTNRYHL,RSVCTRTAKI,Y HLSDCLCPY,CPYRGGYDSL,WPDKLCCSIL,RTAKIWCEGW RPL6 c.578T>G p.F193C LASGLLLVTGPLVLNRVPLRRTHQK[p.F CVIATSTKI,RTHQKCVIA,KCVIATSTK,HQKCVIATS, CRC 193C]CVIATSTKIDISNVKIPKHLTDAYFK RTHQKCVIAT,HQKCVIATST RPRD2 c.289C>A p.R97S PHRLNLFYLANDVIQNCKRKNAIIF[p.R9 AIIFSESFA,NAIIFSESF,FSESFADVL,IIFSESFADV, LUAD 7S]SESFADVLPEAAALVKDPSVSKSVER IFSESFADVL,NAIIFSESFA,KNAIIFSESF RPS2 c.598A>G p.R200G GKPHTVPCKVTGRCGSVLVRLIPAP[p.R RLIPAPGGT,LVRLIPAPG,IPAPGGTGI,LIPAPGGTGI, CLL 200G]GGTGIVSAPVPKKLLMMAGIDDCYTS IPAPGGTGIV RPS6KA5 c.496G>A p.E166K THLSQRERFTEHEVQIYVGEIVLAL[p. VLALKHLHK,LALKHLHKL,LKHLHKLGI,VLALKHLHKL,ALKH CRC E166K]KHLHKLGIIYRDIKLENILLDSNGHV LHKLGI,IVLALKHLHK,YVGEIVLALK,KHLHKLGIIY, GEIVLALKHL,LKHLHKLGII RPS6KA6 c.1181C>A p.S394Y ATSIAEEYKITPITSANVLPIVQIN[p. ENAAQFGEV,QINENAAQF,VQINENAAQ,VQINENAAQF,EN UCEC S394Y]ENAAQFGEVYELKEDIGVGSYSVCKR AAQFGEVY,NENAAQFGEV,LPIVQINENA RPS6KA6 c.327de|A p.K109fs KKASLKVRDRVRTKMERDILVEVNH[p. ILVEVNHHL,LLSNCTMPF,LSNCTMPFR,HHLLSNCTM,ILVEV STAD K109fs]HLLSNCTMPFRLKGNCT* NHHLL,LLSNCTMPFR,SNCTMPFRLK,HLLSNCTMPF, NHHLLSNCTM RPSA c.331C>G p.Q111E AVLKFAAATGATPIAGRFTPGTFTN[p.Q FTNEIQAAF,TPGTFTNEI,FTPGTFTNEI,TFTNEIQAAF,EIQ GBM 111E]EIQAAFWEPRLLVVTDPRADHQPLTE AAFWEPR,NEIQAAFWEP,FTNEIQAAFW RPTN C.1090G>A p.G364S QSSHYGQMDRKGQCYHYDQTNRQGQ[p. SSHYSQPNR,TNRQGQSSHY,GQSSHYSQPN CLL G364S]SSHYSQPNRQGQSSHYGQPDTQDQSS RPTN C.1614G>A p.M538I QTDRQGQSFHYGQPDRQGQSSHYSQ[p. GQSSHYSQI,SSHYSQIDR,SQIDRQGQSS,IDRQGQSSHY TGCT M538I]IDRQGQSSHYGQTDRQGQSSHYGQTD RPTN c.886G>A p.G296S CGQSERLGQELGCGQTDRQGQSSHY[p. SQTDRQDQSY PRAD G296S]SQTDRQDQSYFIYGQTDRQGQSSHYSQ RRAD c.833C>A p.A278E LRRDSKEANARRQAGTRRRESLGKK[p. KEKRFLGRI,KEKRFLGRIV KIRC,TGCT A278E]EKRFLGRIVARNSRKMAFRAKSKSCH RREB1 c.2348G>T p.G783V CGEDLKHYRALRIHMRTHCGRGLGG[p. GVHKGRKPF,CGRGLGGVHK ACC G783V]VHKGRKPFECKECSAAFAAKRNCIHH RRN3 c.25C>T p.R9C MAAPLLHT[p.R9C]CLPGDAAASSSAVK MAAPLLHTC,LLHTCLPGDA,MAAPLLHTCL,HTCLPGDAAA KIRP KLGASRTGISNM RRN3 c.31C>T p.P11S MAAPLLHTRL[p.P11S]SGDAAASSSAV HTRLSGDAA,LLHTRLSGDA,HTRLSGDAAA KIRP KKLGASRTGISNMRA RRP15 c.642G>T p.L214F KEAGSSMRKRAKLISTVSKKDFISV[p.L2 SKKDFISVF,VSKKDFISVF,KDFISVFRGM LUSC 14F]FRGMDGSTNETASSRKKPKAKQTEVK RRS1 c.135de|C p.N45fs QRITVHKELELQFDLGNLLASDRNP[p.N45fs] GSCPRSAWK,STSCGSCPR,RRRPSYRPW,SYRPWRGTT,LLA STAD RPGCGAPDPRRRPSYRPWRGTTR SDRNPR,APDPRRRPS,CGSCPRSAW,SSTSCGSCPR,CGSCP NCSSTSCGSCPRSAWKRR* RSAWK,GSCPRSAWKR,RRRPSYRPWR,SYRPWRGTTR,NL LASDRNPR,APDPRRRPSY,RPSYRPWRGT,RPWRGTTRNC RSBN1 C.1714G>A p.E572K SPFKRRRSMNEIKNLQYLPRTSEPR[p.E572K] RTSEPRKVL,RTSEPRKVLF,LPRTSEPRKV UCEC KVLFEDRTRAFIADHVGQGFDWQSTAA RSF1 c.1158de|A p.K386fs HEITEKSTEETEKLKNDQQAKIPLK[p.K3 QAKIPLKNEK,AKIPLKNEKL STAD 86fs]NEKLN* RSPO2 c.82C>T p.R28C FRLFSFALIILNCMDYSHCQGNRWR[p. QGNRWRCSK,RWRCSKRAS,RCSKRASYV,WRCSKRASY,CQG CRC R28C]CSKRASYVSNPICKGCLSCSKDNGCS NRWRCSK,RWRCSKRASY,QGNRWRCSKR RTN1 c.308C>G p.S103W ASTGVAGVSSAMDHTFSTTSKDGEG[p. EGWCYTSLI,GEGWCYTSL,TSKDGEGWCY,GEG LUAD S103W]WCYTSLISDICYPPQEDSTYFTGILQ WCYTSLI RTN2 c.938de|C p.P313fs KTVPILELSPPLWTAIGWVQRGPTP[p.P VQRGPTPLL,PLLLSSGFY,WVQRGPTPL,TPLLLSSGF,VQRG STAD 313fs]LLLSSGFY* PTPLLL,GWVQRGPTPL,TPLLLSSGFY RUNX1 c.286_287 p.D96fs LCSVLPTHWRCNKTLPIAFKVVALG[p.D VVALGGCSR,VALGGCSRW,KVVALGGCSR,RWHSGHCDGW BRCA insG 96fs]GCSRWHSGHCDGWQ* RUNX1 c.403A>G p.R135G DENYSAELRNATAAMKNQVARFNDL[p. LGFVGRSGR,VARFNDLGF,VARFNDLG LAML R135G]GFVGRSGRGKSFTLTITVFTNPPQVA FV,RFNDLGFVGR,DLGFVGRSGR,QVARFNDLGF RUNX1 c.424_425 p.R142fs LRNATAAMKNQVARFNDLRFVGRSG[p. KLHSDHHCL,CLHKPTASR,HSDHHCLHK,SGWAPRTSK,VG BRCA insA R142fs]KREKLHSDHHCLHKPTASRH RSGKREK,ASRHLPQSH,RTSKTSAET,RFVGRSGKR,QNHS LPQSHQNHSGWAPRTSKTSAETR* GWAPR,APRTSKTSA,QSHQNHSGW,HQNHSGWAP,HSGW APRTSK,RTSKTSAETR,KLHSDHHCLH,HQNHSGWAPR, HCLHKPTASR,LHKPTASRHL RUNX2 c.1010G>T p.R337M SPSIHSTTPLSSTRGTGLPAITDVP[p.R3 AITDVPMRI,LPAITDVPM,GLPAITDVPM LUAD 37M]MRISDDDTATSDFCLWPSTLSKKSQA RUNX2 c.1397C>A p.P466H STPYLYYGTSSGSYQFPMVPGGDRS[p. RSHSRMLPP,HSRMLPPCT,RSHSRMLPPC,HSRMLPPCTT KIRC P466H]HSRMLPPCTTTSNGSTLLNPNLPNQN RUNX2 c.211C>G p.Q71E VAAQQQQQQQQQQQQQQQQQQQ QQQQEEAAA,QQQEEAAAA,QQEEAAAAA,QQQQEEAAA KIRP,TGCT QQQ[p.Q71E]EEAAAAAAAAAAAAAA A,QQQEEAAAAA,QQEEAAAAAA,QEEAAAAAAA AAAVPRLRPP RUSC2 c.1456de|C p.P486fs SSTQAAAAVGPTVLEGQVYTNTSPP[p. AMIAACSAA,MIAACSAAL,AALLSAWAR,ALLSAWARW,N STAD P486fs]TSALDVSAPAAMIAACSAALL TSPPTSAL,SALDVSAPA,DVSAPAAMI,SAPAAMIAA,IAACS SAWARWNVC* AALL,SAALLSAWA,LSAWARWNV,APAAMIAAC,LDVSAP AAM,CSAALLSAW,AMIAACSAAL,MIAACSAALL,LLSAWA RWNV,SAALLSAWAR,YTNTSPPTSA,TSALDVSAPA,DVSAP AAMIA,CSAALLSAWA,ALDVSAPAAM,AAMIAACSAA,ACS AALLSAW,AALLSAWARW RUVBL1 c.1291G>A p.E431K SVQLLTPANLLAKINGKDSIEKEHV[p.E4 HVKEISELF,VKEISELFY,IEKEHVKEI,HVKEISELFY, CRC 31K]KEISELFYDAKSSAKILADQQDKYMK KEHVKEISEL,KEISELFYDA RUVBL1 c.349C>T p.R117C PFCPMVGSEVYSTEIKKTEVLMENF[p.R VLMENFCRA,EVLMENFCR,NFCRAIGLR,LMENFCRAI,VL CRC 117C]CRAIGLRIKETKEVYEGEVTELTPCE MENFCRAI,NFCRAIGLRI,FCRAIGLRIK,ENFCRAIGLR,EVL MENFCRA,MENFCRAIGL RWDD2B c.761G>A p.R254H VEGPQSACEEFWSRLRKLNWKRILI[p.R ILIHHREDI,IHHREDIPF,KLNWKRILIH,RILIHHREDEI,NWKRI CRC 254H]HHREDIPFDGTNDETERQRKFSIFEE LIHHR,LIHHREDIPF RXFP1 c.668C>A p.S223Y HRLEWLIIEDNHLSRISPPTFYGLN[p.S2 GLNYLILLV,TFYGLNYLI,FYGLNYLIL,YGLNYLILL,NYLILLVL UCEC 23Y]YLILLVLMNNVLTRLPDKPLCQHMPR M,LNYLILLVL,YGLNYLILLV,GLNYLILLVL,TFYGLNYLIL,FYG LNYLILL,LNYLILLVLM,SPPTFYGLNY RXRA c.1280C>A p.S427Y AYCKHKYPEQPGRFAKLLLRLPALR[p.S LLRLPALRY,LPALRYIGL,LRYIGLKCL,RLPALRYIGL,LLRLPAL BLCA 427Y]YIGLKCLEHLFFFKLIGDTPIDTFLM RYI,ALRYIGLKCL,YIGLKCLEHL,LLLRLPALRY RXRA c.1280C>T p.S427F AYCKHKYPEQPGRFAKLLLRLPALR[p.S LPALRFIGL,LLRLPALRF,LRFIGLKCL,RLPALRFIGL,FIG BLCA 427F]FIGLKCLEHLFFFKLIGDTPIDTFLM LKCLEHL,LLRLPALRFI,LLLRLPALRF RYR1 c.2002G>T p.D668Y IRPNIFVGRAEGTTQYSKWYFEVMV[p. MVYEVTPFL,KWYFEVMVY,VMVYEVTPF,YEVTPFLTA, TGCT D668Y]YEVTPFLTAQATHLRVGWALTEGYTP FEVMVYEVT,WYFEVMVYEV,VMVYEVTPFL,MVYEVTPFLT,EV MVYEVTPF,SKWYFEVMVY,YEVTPFLTAQ,FEVMVYEVTP RYR1 c.7726G>A p.A2576T NRYLCLAVLPLITKCAPLFAGTEHR[p.A2 RTIMVDSML,HRTIMVDSM,RTIMVDSMLH,LFAGTEHRTI, UCEC 576T]TIMVDSMLHTVYRLSRGRSLTKAQRD FAGTEHRTIM RYR2 c.13002G>T p.M4334I ICSLLLGGSLVEGAKKIKVAELLAN[p. KVAELLANI,LLANIPDPT,IPDPTQDEV,NIPDPTQDEV,IKVA LUAD M4334I]IPDPTQDEVRGDGEEGERKPLEAALP ELLANI,AELLANIPDP RYR2 c.2131G>A p.E711K VTAEATHLRVGWASTEGYSPYPGGG[p. KEWGGNGVG,SPYPGGGKEW LUSC E711K]KEWGGNGVGDDLFSYGF DGLHLWSGC RYR2 c.6069A>C p.L2023F DFHEDLMTHCGIELDEDGSLDGNSD[p. GSLDGNSDF,SLDGNSDFTI,FTIRGRLLSL TGCT L2023F]FTIRGRLLSLVEKVTYLKKKQAEKPV RYR2 c.7239G>C p.K2413N IMTFYSALIDLLGRCAPEMHLIHAG[p.K LIHAGNGEA,IHAGNGEAI,HLIHAGNGEA,LIHAGNGEAI LUAD 2413N]NGEAIRIRSILRSLIPLGDLVGVISI RYR3 c.5008C>A p.P1670T DESKRHGLPGVGLRTCLKPGFRFST[p.P RFSTTCFVV,GFRFSTTCF,FRFSTTCFV,GFRFSTTCFV,PGFRF LUAD 1670T]TCFVVTGEDHQKQSPEIPLESLRTKA STTCF,FRFSTTCFVV RYR3 c.8114G>A p.R2705Q LAVGWTVERTKEGEALVQQRENEKL[p. RENEKLQSV,RENEKLQSVS,NEKLQSVSQA CRC R2705Q]QSVSQANQGNSYSPAPLDLSNVVLSR SACS c.8717G>A p.R2906Q FHVNGHFALDSARRNLWRDDNGVGV[p. QSDWNNSLM,VQSDWNNSL,VQSDWNNSLM UCEC R2906Q]QSDWNNSLMTALIAPAYVELLIQLKK SAFB c.2393de|G p.W798fs REGQHYPERHGGPERHGRDSRDGWG[p. DSRDGWGAM,RDGWGAMAL,DGWGAMALTR,RDSRDG STAD W798fs]AMALTRG* WGAM,SRDGWGAMAL SAFB c.2396G>T p.G799V EREGQHYPERHGGPERHGRDSRDGW[p. DSRDGWVGY,VGYGSDKRM,RDSRDGWVGY TGCT G799V]VGYGSDKRMSEGRGLPPPPRGRRDWG SAGE1 c.685C>T p.R229C HNVCEQKMENVQPAPDNVLLTLRPR[p. TLRPRCINM,RPRCINMTDT,RCINMTDTGI CRC R229C]CINMTDTGISPMSTRDPYATITYNVP SAGE1 c.894C>A p.H298Q STGLINVAGAGTPAISTNGLYSTVP[p. LYSTVPQNV,GLYSTVPQNV LUAD H298Q]QNVCEEKMENDQPQPNNVLSTVQPVI SALL3 c.1777C>G p.L593V PGLNHVESGVSATAESPQSLLGGPP[p.L SLLGGPPVT,LLGGPPVTK,LLGGPPVTKA,SLLGGPPVTK ACC 593V]VTKAEPVSLPCTNARAGDAPVGAQAS SALL4 c.2983de|G p.V995fs NQYTSMLNGGLAVKTNEISVIQSGG[p. FLPSRFPWG,GFLPSRFPW,RFPWGPPPL,ISVIQSGGF,IQSG STAD V995fs]FLPSRFPWGPPPL* GFLPS,SGGFLPSRF,SRFPWGPPP,FLPSRFPWGP,QSGGFL PSRF,GGFLPSRFPW,SRFPWGPPPL SALL4 c.560G>T p.R187L PPTPQDISYLAKGKVANTNVTLQAL[p.R ALLGTKVAV,LQALLGTKV,TLQALLGTK,TLQALLGTKV,VTL LUAD 187L]LGTKVAVNQRSADALPAPVPGANSIP QALLGTK,NTNVTLQALL,LQALLGTKVA SAMD3 c.618G>T p.Q206H DMTKYLEGSLYPSTQQYNDVVNALL[p. ALLHAHPFL,NALLHAHPF,VNALLHAHPF LUSC Q206H]HAHPFLDEDGCGFFLWKRALKDRFKY SAMD4B c.1429C>T p.R477W APAPTDGSEPAPAPVADGDIPSQFT[p. SQFTWVMGK,DIPSQFTWV,IPSQFTWVM,GDIPSQFTW,S UCS R477W]WVMGKVCTQLLVSRPDEENITSYLQL QFTWVMGKV,WVMGKVCTQL,PSQFTWVMGK,DIPSQFT WVM SBF1 c.3228de|C p.P1076fs SRNLVKNAKKTIGRQHVTRKKYNPP[p. STGASRPLR,ASRPLRTRR,RTRRTRSQC,RTRSQCRRS,RSQC STAD P1076fs]AGSTGASRPLRTRRTRSQCRRSW RRSWS,VTRKKYNPPA,ASRPLRTRRT,RTRRTRSACR,RTRS SPAR* QCRRSW,RSQCRRSWSP,QCRRSWSPAR,RPLRTRRTRS,KK YNPPAGST,SQCRRSWSPA SBNO1 c.3415_341 p.N1139fs EVHQQNALFQYFADTLTAVVQNAKK[p. AVVQNAKKK,VQNAKKKWK,VVQNAKKKWK STAD 6insA N1139fs]KWKI* SBSPON c.397G>T p.G133W GGAPCPPLEERAGCLEYSTPQGQDC[p. GQDCWHTYV,CWHTYVPAF,QGQDCWHTY,CWHTYVPAF LUAD G133W]WHTYVPAFITTSAFNKERTRQATSPH I,PQGQDCWHTY,YSTPQGQDCW SCAF1 c.624_625 p.P208fs PPPAPSSASSSPSPSPSSSSPSPPP[p.P2 SPSPPPTPT,TPSPTCPPI,SPTCPPIRY,CTPSPTCPPI,SPSPPP KIRC insC 08fs]TPTAPCTPSPTCPPIRYL* TPTA,SPTCPPIRYL SCAF11 c.2776_277 p.E926fs SSPGEKSRSQSRERESDRDGQRRER[p.E RERKENQKV,RERKENQKVV GBM,KIRP 7de|GA 926fs]KENQKVV* SCAF8 c.2218G>T p.G740C LVQPSLSMTPETVKDVGFGSLVIPG[p.G SLVIPGCSV,LVIPGCSVA,SLVIPGCSVA,IPGCSVASNL LUAD 740C]CSVASNLATSALPAGNVFNAPTKQAE SCAPER C.1097G>A p.R366Q AEKTQFTVSTLDDVKNSGSIRDNYV[p.R VQTSEISAV,YVQTSEISAV,QTSEISAVHI,RDNYVQTSEI,VQ UCEC 366Q]QTSEISAVHIDTECVSVMLQAGTPPL TSEISAVH SCARF1 c.1841G>A p.R614Q SVSFAEGTKFAPQSRRSSGELSSPL[p.R6 LSSPLQKPK,LQKPKRLSR,SPLQKPKRL STAD 14Q]QKPKRLSRGAQSGPEGREAEESTGPE SCFD2 c.1633C>T p.R545W TDWDSSINLTFHKSKIAVDELFTSL[p.R5 ELFTSLWDI,SLWDIAGAR,TSLWDIAGA,WDIAGARSL,FTSL CRC 45W]WDIAGARSLLKQFKSVYVPGNHT WDIAGA,ELFTSLWDIA,TSLWDIAGAR,WDIAGARSLL,DEL HQA FTSLWDI SCLT1 c.327de|A p.K109fs MKLQLENVIKENERLHSELKDAVEK[p.K KNWRPFPWA,AVEKNWRPF,EKNWRPFPW,NWRPFPWA STAD 109fs]NWRPFPWAQR* QR,VEKNWRPFPW,DAVEKNWRPF SCML4 c.581G>A p.R194Q GKQHLRSLPVVNSIGYVLRFLAKLC[p.R FLAKLCQSL,FLAKLCQSLL,RFLAKLCQSL,CQSLLCDDLF CRC 194Q]QSLLCDDLFSHQPFPRGCSASEKVQE SCML4 c.783G>T p.L261F YLVNPVGMNRYSVDTSASTFNHRGS[p. STFNHRGSF,SFHPSSSLY,GSFHPSSSL,STFNHRGSFH,GSFH LUAD L261F]FHPSSSLYCKRQNSGDSHLGGGPAAT PSSSLY,RGSFHPSSSL,ASTFNHRGSF SCN10A c.3425G>A p.R1142H EGCIRHCPCCKLDTTKSPWDVGWQV[p. WQVHKTCYR,WQVHKTCYRI,VGWQVHKTCY,SPWDVGW MM R1142H]HKTCYRIVEHSWFESFIIFMILLSSG QVH SCN10A c.4709C>T p.T1570M IVVVLSIASLIFSAILKSLQSYFSP[p.T157 SLQSYFSPM,LQSYFSPML,YFSPMLFRV,MLFRVIRLA,SYFSP CRC 0M]MLFRVIRLARIGRILRLIRAAKGIRT MLFR,QSYFSPMLF,SPMLFRVIR,SLQSYFSPML, QSYFSPMLFR,MLFRVIRLAR,LQSYFSPMLF,SYFSPMLFRV, YFSPMLFRVI,KSLQSYFSPM,FSPMLFRVIR,SPMLFRVIRL SCN2A c.107G>A p.R36K PDSFRFFTRESLAAIEQRIAEEKAK[p.R3 RIAEEKAKK,KAKKPKQER,KAKKPKQERK BRCA 6K]KPKQERKDEDDENGPKPNSDLEAGKS SCN2A c.464C>A p.T155K LFNMLIMCTILTNCVFMTMSNPPDW[p. TMSNPPDWK,MSNPPDWKK,WKKNVEYTF,MTMSNPPD LUAD T155K]KKNVEYTFTGIYTFESLIKILARGFC WK,TMSNPPDWKK,DWKKNVEYTF SCN7A c.4073G>A p.R1358H MTVGSYLVPPSLVQLILLSRIIHML[p. IIHMLHLGK,MLHLGKGPK,LSRIIHMLH,SRIIHMLHL,HLGK GBM R1358H]HLGKGPKVFHNLMLPLMLSLPAL GPKVF,MLHLGKGPKV,RIIHMLHLGK,HMLHLGKGPK,LSRII LNI HMLHL,LHLGKGPKVF SCNN1G c.1691G>A p.R564H MSCSVVCVIEIIEVFFIDFFSIIAR[p.R564 IIARHQWQK,IARHQWQKA,DFFSIIARH,FSIIARHQW,HQ GBM H]HQWQKAKEWWAWKQAPPCPEAP WQKAKEW,IIARHQWQKA,SIIARHQWQK,FFSIIARHQW,I RSPQ ARHQWQKAK,HQWQKAKEWW SCRIB c.995G>T p.G332V SLGKLTKLTNLNVDRNHLEALPPEI[p.G IVGCVALSV,ALPPEIVGC,LEALPPEIV,PEIVG TGCT 332V]VGCVALSVLSLRDNRLAVLPPELAHT CV,ALPPEIVGCV,ALPPEIVGCV,EIVGCVALSV,LPPEIVGCVA SCRT1 c.397T>G p.S133A VSEGYAADAFFITDGRSRRKASNAG[p.S RRKASNAGA,KASNAGAAA,RKASNAGAA,KAS ACC 133A]AAAAPSTASAAAPDGDAGGGGGAGGR NAGAAAA,RKASNAGAAA,AAAAPSTASA SCUBE2 c.1024G>A p.V342M DGKTCKDIDECQTRNGGCDHFCKNI[p. FCKNIMGSF,CDHFCKNIM,IMGSFDCGCK,HFCKNIMGSF CRC V342M]MGSFDCGCKKGFKLLTDEKSCQDVDE SDAD1 c.824de|A p.K275fs YATGKKSSKNKKKLEKAMKVLKKQK[p. KVLKKQKRR,VLKKQKRRK,KQKRRKNQR,RKNQRCLTF,QR STAD K275fs]RRKNQRCLTFQPFT* CLTFQPF,KVLKKQKRRK,AMKVLKKQKR,NQRCLTFQPF,RR KNQRCLTF SDHAP1 c.196C>T p.H66Y DYKVRIDEYDHSKPIQGQQKKPFEE[p.H YWRKHTLSY,QQKKPFEEY,EEYWRKHTL,EYWRKHTLSY,Y CESC 66Y]YWRKHTLSYVDVSTGKVTVEYRPIID WRKHTLSYV,GQQKKPFEEY,QQKKPFEEYW,FEEYWRKHTL SDHAP2 c.110_111 p.S37fs VGRPPVPLHMVSTASGQTRCWTWLS[p. CWTWLSLVR,TRCWTWLSL,WTWLSLVRHV,QTRCWTWLSL CESC insTT S37fs]LVRHVP* SDHAP2 c.91C>T p.R31C LCPACTPVGRPPVPLHMVSTASGQT[p. SGQTCCWTW,GQTCCWTWL,TASGQTCCW GBM,PRAD R31C]CCWTWLSGQACALSIAESCRPGDKVP SDHAP3 c.196G>A p.A66T AACASVHGANRLGANSLLDLVVFGQ[p. VVFGQTCAL,FGQTCALSI,VFGQTCALSI,LVVFGQTCAL GBM A66T]TCALSIEESCRPGDKVPPIKPNAGEE SDK1 c.1524_1525 p.K508fs RPVDTTVTDGMTAILRCEVSGAPKP[p. EVSGAPKPR,KRKPHSGQW,RKPHSGQWL,APKPRHHLEK, KIRC insC K508fs]RHHLEKRKPHSGQWLCPDS* KPRHHLEKRK,KRKPHSGQWL SDK1 c.3542C>T p.T1181M PSPYSPSSRVIQTLQAPPDVAPTSV[p. DVAPTSVMV,MVRTASETSL,DVAPTSVMVR,APTSVMVRTA CRC T1181M]MVRTASETSLRLRWVPLPDSQYNGNP SDK1 c.6437A>G p.Y2146C ADASESEATDSDYEDALPKHSFVNH[p. HCMSDPTYY,KHSFVNHCM,NHCMSDPTY, TGCT Y2146C]CMSDPTYYNSWKRRAQGRAP FVNHCMSDPT,VNHCMSDPTY APHRYE SEC24D c.150_151 p.A50fs YGHYGDPSHTASPTGMMKPAGPLGA[p. MKPAGPLGAH LUAD insC A50fs]HRH* SEC31B c.2713C>T p.P905S GVRPASSQPQLLGGQRVQVPNPVGF[p. VGFSGTWPL,NPVGFSGTW TGCT P905S]SGTWPLPGSPLPMACPGIMRP GSTSL SEC61A2 c.377G>T p.G126V EVGDTPKDRALFNGAQKLFGMIITI[p.G ITIVQAIVY,MIITIVQAI,TIVQAIVYV,GMIITIVQA,IITIVQAIV, LUAD 126V]VQAIVYVMTGMYGDPAEMGAG IVQAIVYVM,KLFGMIITIV,GMIITIVQAI,MIITIVQAIV,ITIV ICLLI QAIVYVL,IITIVQAIVY,TIVQAIVYVM SECISBP2 c.1824C>G p.D608E GMDELISTPSVEDKSEEPPGTELQR[p.D LQRETEASH,RETEASHLA,TELQRETEA,LQRETEASFIL,RETE KIRC 608E]ETEASHLAPNHTTFPKIHSRRFRD ASHLAP YC SELP c.1285C>T p.R429W RAFQYDTNCSFRCAEGFMLRGADIV[p. VWCDNLGQW,MLRGADIVW,FMLRGADIVW,IVWCDNL UCEC R429W]WCDNLGQWTAPAPVCQALQ GQW CQDLPVP SELP c.889G>A p.A297T NMTCLHSAKAFQHQSSCSFSCEEGF[p. FTLVGPEVV,FSCEEGFTL,FSCEEGFTLV,EGFTLVGPEV TGCT A297T]TLVGPEVVQCTASGVWTAPAP VCKAV SEMA3A c.241G>A p.D81N SYHTFLLDEERSRLYVGAKDHIFSF[p.D8 FSFNLVNIK,IFSFNLVNI,KDHIFSFNL,HIFSFNLVNI,NLVNIK CRC 1N]NLVNIKDFQKIVWPVSYTRRDECK DFQK,SFNLVNIKDF,KDHIFSFNLV WA SEMA4D c.755G>A p.R252Q EDDRVYFFFTEVSVEYEFVFRVLIP[p.R2 VLIPQIARV,RVLIPQIAR,FVFRVLIPQI,RVLIPQIARV,VFRVLI CRC 52Q]QIARVCKGDQGGLRTLQKKWTSF PQIA LKA SEMG2 c.874C>T p.R292C QHQTKNLSQDQEHGRKAHKISYPSS[p. CTEERQLHH,HKISYPSSC GBM R292C]CTEERQLHHGEKSVQKDVSKGS ISIQ SENP7 c.2018C>A p.S673Y ELELSYPLSWVQAFPLFQNLSSKES[p.S6 SYFIHYYCV,SSKESYFIH,KESYFIHYY,ESYFIHYYC,QNLSSKES UCEC 73Y]YFIHYYCVSTCSFPAGVAVAEEMKL Y,NLSSKESYF,SKESYFIHY,NLSSKESYFI,SSKESYFIHY,FQNL K SSKESY,SKESYFIHYY,ESYFIHYYCV,QNLSS KESYF,KESYFIHYYC SEPHS1 c.1112G>A p.R371Q GEGHQAWIIGIVEKGNRTARIIDKP[p.R QIIEVAPQV,RIIDKPQII,IIDKPQIIEV CRC 371Q]QIIEVAPQVATQNVNPTPGATS* SEPHS1 c.37G>A p.E13K MSTRESFNPESY[p.E13K]KLDKSFRLTR ESFNPESYK,SFNPESYKL,SYKLDKSFR,ESYKLDKSF,YKLDKS UCEC FTELKGTGCKVPQDVL FRL,KLDKSFRLTR,SYKLDKSFRL,ESYKLDKSFR,ESFNPESYKL SERPIN c.631C>G p.R211G HGKINNLIENIDPGTVMLLANYIFF[p.R2 LLANYIFFG,YIFFGARWK,NYIFFGARW,FGARWKHEF,ANYI BLCA A12 11G]GARWKHEFDPNVTKEEDFFLEKN FFGAR,LANYIFFGA,MLLANYIFFG,LLANYIFFGA,LANYIFFG SSV AR,FFGARWKHEF,ANYIFFGARW SERPIN c.757G>T p.D253Y FFLEKNSSVKVPMMFRSGIYQVGYD[p. YQVGYDYKL,GIYQVGYDY,YDYKLSCTI,GIYQVGYDYK,IYQ LUAD A12 D253Y]YKLSCTILEIPYQKNITAIFILPDEG VGYDYKL,SGIYQVGYDY,YDYKLSCTIL,YKLSCTILEI SERPINA3 c.474G>C p.K158N LQLSMGNAMFVKEQLSLLDRFTEDA[p. FTEDANRLY,NRLYGSEAF,RFTEDANRLY,ANRLYGSEAF CESC K158N]NRLYGSEAFATDFQDSAAAKKL INDY SERPINA4 c.292C>T p.R98C HQQILETGEGSPSLKIAPANADFAF[p.R NADFAFCFY,FAFCFYYLI,DFAFCFYYL,ADFAFCFYY,ANADF CESC 98C]CFYYLIASETPGKNIFFSPLSISAAY AFCF,NADFAFCFYY,FAFCFYYLIA,DFAFCFYYLI,ANADFAFC FY,ADFAFCFYYL SERPINA9 c.1242G>T p.M414I TTKFIVRSKDGPSYFTVSFNRTFLM[p.M FLMIITNKA,TFLMIITNK,SFNRTFLMI,FNRTFLMII,FLMIITN LUAD 414I]IITNKATDGILFLGKVENPTKS* KAT,RTFLMIITNK,VSFNRTFLMI,SFNRTFLMII SERPIN c.503de|A p.Q168fs PICQEYLDGVIQFYHTTIESVDFQK[p.Q NSSARTLLM,SVDFQKTLK,KTLKNPDKR,TSGLNVNPK,SAR STAD B12 168fs]TLKNPDKRLTSGLNVNPKVKSRNS TLLMLR,LMLRLCWYW,KVKSRNSSA,KSRNSSART,RNSSA SARTLLMLRLCWYW* RTLL,LLMLRLCWY,NVNPKVKSR,KRLTSGLNV,SRNSSARTL, SSARTLLML,IESVDFQKT,LTSGLNVNPK,SSARTLLMLR,RT LLMLRLCW,LLMLRLCWYW,FQKTLKNPDK,SGLNVNPKVK, KVKSRNSSAR,KSRNSSARTL,RNSSARTLLM,SARTLLMLRL, TLLMLRLCWY,NPDKRLTSGL,IESVDFQKTL,SRNSSARTLL SERPINB3 c.626C>G p.S209C GQWENKFKKENTKEEKFWPNKNTYK[p. KCVQMMRQY,TYKCVQMMR,NTYKCVQMM, KIRC S209C]CVQMMRQYNSFNFALLEDV NTYKCVQMMR,WPNKNTYKCV,NKNTYKCVQM, QAKVLEI YKCVQMMRQY SERPINC1 c.134G>T p.R45L SLLLIGFWDCVTCHGSPVDICTAKP[p.R TAKPLDIPM,VDICTAKPL,CTAKPLDIPM,KPLDIPMNPM LUAD 45L]LDIPMNPMCIYRSPEKKATEDEGS EQ SERPINI1 c.243de|A p.L81fs GMMELGAQGSTQKEIRHSMGYDSLK[p. SLKMVKNFL,SMGYDSLKM,SMGYDSLKMV,MGYDSLKMV STAD L81fs]MVKNFLS* K,SLKMVKNFLS,HSMGYDSLKM SESTD1 c.918T>G p.I306M VMQVVNWLEGPGSEQLRAQWGIGDS[p.I3 SMRASQALA,DSMRASQAL,AQWGIGDSM,SMRASQALQ KIRC 06M]MRASQALQQKHEEIESQHS Q,RAQWGIGDSM EWFAVYV SETDB2 c.2145de|A p.R715fs YGYEAGTVPEKEIFCQCGVNKCRKK[p.R KYYKYVTNA,KCRKKYYKY,GVNKCRKKY,YKYVTNACL,KYYK STAD 715fs]YYKYVTNACL* YVTNAC,YYKYVTNACL,VNKCRKKYYK,KCRKKYY KYV,GVNKCRKKYY,KKYYKYVTNA SEZ6L c.620C>T p.S207L VPLWLDRKESAVPTTPAPLQISPFT[p.S TLQPYVAHT,LQPYVAHTL,ISPFTLQPY,LQISPFTLQ,SPFTLQ CRC 207L]LQPYVAHTLPQRPEPGEPGPDM PYV,TLQPYVAHTL,QISPFTLQPY,ISPFTLQPYV,APLQISPFT AQEA L,LQISPFTLQP,SPFTLQPYVA SEZ6L2 c.221G>C p.R74P EALAELLHGALLRRGPEMGYLPGSD[p. YLPGSDPDPT,LPGSDPDPTL ACC R74P]PDPTLATPPAGQTLAVPSLPRAT EPG SF1 c.763C>T p.R255W IETPEDQNDLRKMQLRELARLNGTL[p. TLWEDDNRI,LARLNGTLW,TLWEDDNRIL CESC R255W]WEDDNRILRPWQSSETRSITN TTVCT SF3B1 c.1868A>G p.Y623C SNLAKAAGLATMISTMRPDIDNMDE[p. CVRNTTARA,CVRNTTARAF CLL Y623C]CVRNTTARAFAVVASALGIPSL LPFL SF3B1 c.1876A>T p.N626Y AKAAGLATMISTMRPDIDNMDEYVR[p. NMDEYVRYT,YTTARAFAV,YVRYTTARA,RYTTARAFA,EYV CLL N626Y]YTTARAFAVVASALGIPSLLPFL RYTTAR,VRYTTARAF,DEYVRYTTA,NMDEYVRYTT,YTTAR KAV AFAVV,RYTTARAFAV,YVRYTTARAF,IDNMDEYVRY,DEYV RYTTAR SF3B1 c.1996A>G p.K666E IPSLLPFLKAVCKSKKSWQARHTGI[p.K6 QARHTGIEI,EIVQQIAIL,IEIVQQIAI,WQARHTGIEI,EIVQQI CLL 66E]EIVQQIAILMGCAILPHLRSLVEIIE AILM,IEIVQQIAIL SF3B1 c.2098A>G p.K700E MGCAILPHLRSLVEIIEFIGLVDEQQ[p.K GLVDEQQEV,EVRTISALA,QEVRTISAL,DEQQEVRTI,EVRTI BRCA,CLL 700E]EVRTISALAIAALAEAATPYGIESFD SALAI,QQEVRTISAL,DEQQEVRTIS,QEVRTISALA SF3B1 c.2704G>A P.E902K GNLGAADIDHKLEEQLIDGILYAFQ[p.E ILYAFQKQT,KQTTEDSVM,ILYAFQKQTT, BLCA 902K]KQTTEDSVMLNGFGTVVNALGK FQKQTTEDSV,QKQTTEDSVM,KQTTEDSVML RVKP SF3B1 c.2870G>A p.R957Q ICGTVLWRLNNKSAKVRQQAADLIS[p. DLISQTAVV,ISQTAVVMK,LISQTAVVM,ADLISQTAV,LISQ UCEC R957Q]QTAVVMKTCQEEKLMGFILGV TAVVMK,QAADLISQTA,DLISQTAVVM,RQQAADLISQ VLYEYL SFI1 c.2462G>A p.R821Q THHLQCVRKRLLHRQSTQLLAQRLS[p. LLAQRLSQT,SQTCFRQWR,AQRLSQTCF,LSQTCFRQW,LL HNSC R821Q]QTCFRQWRQQLAARRQEQRA AQRLSQTC,AQRLSQTCFR,LSQTCFRQWR,LAQRLSQTCF,R TVRALW LSQTCFRQW SFPQ c.1832G>A p.R611Q EEQMRRQREESYSRMGYMDPRERDM MQMGGGGAM,DMQMGGGGAM,QMGGGGAMNM,M CRC [p.R611Q]QMGGGGAMNMGDPYGS QMGGGGAMN GGQKFPPLGG SFRP4 c.695G>A p.R232Q QRSGCNEVTTVVDVKEIFKSSSPIP[p.R2 IPQTQVPL,SSSPIPQTQV,SPIPQTQVPL UCEC 32Q]QTQVPLITNSSCQCPHILPHQDVLIM SFSWAP c.1850C>A p.S617Y PLEKNRVKLDDDSDDDEESKEGQES[p. ESKEGQESY,GQESYSSAA,YSSAANTNPA,KEGQESYSSA,EE CRC S617Y]YSSAANTNPAVAPPCVVVEEKK SKEGQESY,QESYSSAANT PQLT SGCG c.659C>T p.A220V ESPTRSLSMDAPRGVHIQAHAGKIE[p. EVLSQMDIL,VLSQMDILF,GKIEVLSQM,IEVLSQMDI,IQAH CRC A220V]VLSQMDILFHSSDGMLVLDAET AGKIEV,QAHAGKIEVL,IEVLSQMDIL,EVLSQMDILF VCLP SGCZ c.123T>G P.I41M REQYILATQQNNLPRTENAQLYPVG[p. LYPVGMYGW,MYGWRKRCL,AQLYPVGMY,GMYGWRKR CRC I41M]MYGWRKRCLYFFVLLLLVTMIVN CL,MYGWRKRCLY,NAQLYPVGMY,QLYPVGMYGW LAM SGIP1 c.1505G>T p.R502L GVGDVSRPFSPPIHSSSPPPIAPLA[p.R5 ALAESTSSI,ALAESTSSIS,SPPPIAPLAL,LALAESTSSI LUAD 02L]LAESTSSISSTNSLSAATTPTVENEQ SGK1 c.1100_1102 p.K367de| AKDDFMEIKSHVFFSLINWDDLINK[p.K LINKITPPF,DLINKITPPF UCEC de|AGA 367de|]ITPPFNPNVSGPNDLRHFDPEF TEEPVP SGK3 c.183de|A p.L61fs SEWFVFRRYAEFDKLYNTLKKQFPA[p.L TLKKQFPAW STAD 61fs]WP* SGOL2 c.1220de|A p.E407fs KKSNKKTNEHGMKTFRKVKDSSSEK[p. LMSWMAKGV,WMAKGVQKI,SLKIVQMSI,IVQMSILGK,M STAD E407fs]REKDQRDSLKIVQMSILGKRLK SILGKRLK,SWMAKGVQK,FSIMNSWLR,GVQKIPVLF,KDL TGQKDLMSWMAKGVQKIPVLFSIMNS MSWMAK,GQKDLMSWM,REKDQRDSL,RDSLKIVQM,LKI WLR* VQMSIL,KGVQKIPVL,QKIPVLFSI,KIPVLFSIM,VLFSIMNS W,DLMSWMAKGV,VLFSIMNSWL,SLKIVQMSIL,KIVQMSI LGK,QMSILGKRLK,MSWMAKGVQK,SWMAKGVQKI,KGV QKIPVLF,KVKDSSSEKR,REKDQRDSLK,LGKRLKTGQK,RLK TGQKDLM,MAKGVQKIPV,IVQMSILGKR,LFSIMNSWLR,V QMSILGKRL,KRLKTGQKDL,GQKDLMSWMA,AKGVQKIPV L,VQKIPVLFSI,QKIPVLFSIM SGSM1 c.2452G>A p.E818K VLDAQRNTPTVLRPRDGSVDDRQSS[p. SVDDRQSSK,RQSSKATTS,GSVDDRQSSK,RQSSKATTSQ CESC E818K]KATTSQDEAPREELAVQDSLES DLLA SGSM1 c.3351C>A p.F1117L IALALVEVYRDIILENNMDFTDIIK[p.F11 FTDIIKLFN,KLFNEMAER,DFTDIIKLF,DIIKLFNEM,MDFTDII CRC 17L]LFNEMAERHNTKQVLKLARDLVYK KL,NMDFTDIIKL,DIIKLFNEMA,MDFTDIIKLF VQ SH3KBP1 c.1688_1689 p.P563fs ISQVSDNKASLPPKPGTMAAGGGGP[p. VLSGALPPV,TQSQLPVSV,GALPPVILF,PVSVRHGRK,SVRH KIRC insC P563fs]SPSVLSGALPPVILFGNSWTQS GRKTK,LPVSVRHGR,SPSVLSGAL,SWTQSQLPV,SQLPVSVR QLPVSVRHGRKTKDGACGQQPGGRG H,SVLSGALPPV,VLSGALPPVI,ILFGNSWTQS,WTQSQLP GAKDTGPRAEEHHRDHEGPAETRD* VSV,VSVRHGRKTK,QLPVSVRHGR,NSWTQSQLPV,SGALP PVILF,FGNSWTQSQL,SQLPVSVRHG,PPVILFGNSW SH3KBP1 c.1720de|C p.L574fs LPPKPGTMAAGGGGPAPLSSAAPSP[p. RWSLRPAAR,RPAARRPWR,CSARKENQR,WSLRPAARR,R STAD L574fs]CHPLWEQLDTEPTPRLCSARKE KENQRWSL,NQRWSLRPA,QRWSLRPAA,WEQLDTEPT,AP NQRWSLRPAARRPWRS* SPCHPLW,RWSLRPAARR,SLRPAARRPW,EQLDTEPTPR,S AAPSPCHPL,RPAARRPWRS,NQRWSLRPAA SH3PX c.2276C>T p.S759L SSDLITLPATTPPCPTKKEWEGPAT[p.S7 TLYMTCSAY,ATLYMTCSA,KEWEGPATL,WEGPATLYM,AT LUAD D2A 59L]LYMTCSAYQKVQDSEISFPAGVEV LYMTCSAY,LYMTCSAYQK,KEWEGPATLY,KKEWEGPATL, QV WEGPATLYMT SH3RF2 c.952C>T p.R318C RKVPGQFSITTALNTLNRMVHSPSG[p. HSPSGCHMV,VHSPSGCHM,MVHSPSGCHM,SPSGCHMV GBM R318C]CHMVEISTPVLISSSNPSVITQP EI,RMVHSPSGCH,CHMVEISTPV MEK SH3TC c.265C>T p.R89C RCVNGPLQEAARRRLWALENEDQEV[p.R NEDQEVCML,CMLFKDLSAR,LENEDQEVCM,NEDQEVCM CRC 2 89]CMLFKDLSARLVSIQSQRAQFLI LF,QEVCMLFKDL TFK SHB c.1378G>A p.A460 RNSQTSKHDYSLSLRSNQGFMHMKL[p. FMHMKLTKT,GFMHMKLTK,KLTKTKEKY,KLTKTKEKYV,F GBM T A460T]TKTKEKYVLGQNSPPFDSVPEV MHMKLTKT,QGFMHMKLTK,HMKLTKTKE,LTKTKEKYV IHYY  L,MKLTKTKEKY SHROOM4 c.3468_3470 p.1156_1 EEEEEEEEEEEEEEEEEEEAEEEEE[p. EEAEEEEEL PAAD de|AGA 157EE>E 1156_1157EE>E]LPPQYFSSETSGSCALN PEEVLEQPQPL SI c.3649G>T p.V1217F LDFYMFLGPTPEVATKQYHEVIGHP[p. FMPAYWALG,PFMPAYWAL,IGHPFMPAY,HPFMPAYWA, LUAD V1217F]FMPAYWALGFQLCRYGYANT YHEVIGHPF,HEVIGHPFM,FMPAYWALGF,QYHEVIGHPF, SEVREL VIGHPFMPAY,EVIGHPFMPA,HPFMPAYWAL,YHEVIGHP FM,IGHPFMPAYW SI c.5042T>A p.I1681K WFDYHTGKDIGVRGQFQTFNASYDT[p. TFNASYDTK,QTFNASYDTK,ASYDTKNLHV TGCT I1681K]KNLHVRGGHILPCQEPAQNTF YSRQK SIGLEC1 c.954de|C p.P318fs QAAWSDAGVYTCQAENGVGSLVSPP[p. SASTSSWLR,STSSWLRSR,PPSASTSSW,ASTSS STAD P318fs]SASTSSWLRSR* WLRSR,SPPSASTSSW SIGLEC10 c.749C>T p.T250M SAQRTVRLRVAYAPRDLVISISRDN[p.T ISRDNMPAL,MPALEPQPQ,SISRDNMPAL,LVISISRDNM, GBM 250M]MPALEPQPQGNVPYLEAQKGQ ISISRDNMPA,MPALEPQPQG FLRLL SIGLEC11 c.1088C>T p.S363F NRLGSQQQALDLSVQYPPENLRVMV[p. MVFQANRTV,RVMVFQANR,VMVFQANRTV, CRC S363F]FQANRTVLENLGNGTSLPVLEG RVMVFQANRT,MVFQANRTVL,FQANRTVLEN QSLR SIK1 c.2032de|C p.Q678fs EVLEQQRLLQLQHHPAAAPGCSQAP[p. QAPSRPLPR,APSRPLPRL,CSQAPSRPL,SQAPSRPLP,SQAP STAD Q678fs]SRPLPRL* SRPLPR SIM1 c.637G>A p.V213M YLKIRQYSLDMSPFDGCYQNVGLVA[p. YQNVGLVAM,GLVAMGHSL,MGHSLPPSA,VAMGHSLPP, CESC V213M]MGHSLPPSAVTEIKLHSNMFM AMGHSLPPSA,CYQNVGLVAM,YQNVGLVAMG,MGHSLP FRASL PSAV SIPA1 c.3188G>A p.R106 SETYRMPVMEYKMNEGVSYEFKFPF[p. KFPFQNNNK,FQNNNKWQR,FPFQNNNKW,YEFKFPFQN, CRC L1 3Q R1063Q]QNNNKWQRNASKGPHSPQ KFPFQNNNKW,YEFKFPFQNN VPSQVQSP SIPA1 c.3680C>A p.S122 PSWQRSEDSIADQMAYSYRGPQDFN[p. RGPQDFNYF,YFVLEQHEY,YRGPQDFNY,YRGPQDFNYF,SY CRC L1 7Y S1227Y]YFVLEQHEYTEPTCHLPAVSK RGPQDFNY,NYFVLEQHEY,GPQDFNYFVL VLPAF SIPA1 c.2330G>C p.G777A RVHNPCTDNVCYSMAVTRSKDAPPF[p. RSKDAPPFA,DAPPFAPPI,RSKDAPPFAP,APPIPSGTTF,KDA KIRC L3 G777A]APPIPSGTTFRKSDVFRDFLLAK PPFAPPI VIN SIRPA c.387_389 p.D131 IRIGNITPADAGTYYCVKFRKGSPD[p.D KGSPDVEFK,KFRKGSPDV,RKGSPDVEF,VKFRKGSPDV,FR KIRC de|CGA de| 131de|]VEFKSGAGTELSVRAKPSAPVV KGSPDVEF SGPAAR SIRPA c.697G>A p.V233I SIHSTAKVVLTREDVHSQVICEVAH[p.V QVICEVAHI,VICEVAHITL,SQVICEVAHI PRAD 233I]ITLQGDPLRGTANLSETIRVPPTLEV SIX1 c.571G>A p.E191K TQVSNWFKNRRQRDRAAEAKERENT[p. KNNNSSSNK UCEC E191K]KNNNSSSNKQNQLSPLEGGK PLMSSS SIX3 c.79A>C p.I27L VFRSPLDLYSSHFLLPNFADSHHRS[p.I2 FADSHHRSL,FADSHHRSLL CLL 7L]LLLASSGGGNGAGGGGGAGGGSG GGN SKI c.185C>G p.A62G AFSARWAQEAYKKESAKEAGAAAVP[p. GAAAVPGPV,KEAGAAAVPG KIRP A62G]GPVPAATEPPPVLHLPAIQPPPP VLP SKOR c.2648A>G p.Y883C EEMVQQLQIVRDTLCNELDQERKAR[p. KARCAIQQK,RCAIQQKLK,QERKARCAI,KARCAIQQKL LUAD 1 Y883C]CAIQQKLKEAHDALHHFSCKML TPRH SLAM c.829de|A p.S277fs LIMVVILQLRRRGKTNHYQTTVEKK[p.S TLAPPYMLL,SMPKSRNQV,KQIPSQSML,QIPSQSMLV,KSR BLCA F1 277fs]ALRSMPKSRNQVLFRRNLTPSQL NQVLFR,SLSQSLSRK,QSLSQSLSR,RTLAPPYML,PYMLLPQ RTLAPPYMLLPQSLSQSLSRKQIPSQSM SL,KKALRSMPK,ALRSMPKSR,RSMPKSRNQ,RNLTPSQLR, LV* QLRTLAPPY,TTVEKKALR,MPKSRNQVL,TPSQLRTLA,LPQS LSQSL,VEKKALRSM,NQVLFRRNL,RRNLTPSQL,SQLRTLAP P,LRTLAPPYM,SQSLSRKQI,RKQIPSQSM,LLPQSLSQSL,KQ IPSQSMLV,SMPKSRNQVL,KSRNQVLFRR,QSLSQSLSRK,R TLAPPYMLL,KALRSMPKSR,RSMPKSRNQV,QLRTLAPPYM, SQLRTLAPPY,QTTVEKKALR,MPKSRNQVLF,PPYMLLPQS L,YQTTVEKKAL,FRRNLTPSQL,YMLLPQSLSQ,SRKQIPSQS M,RKQIPSQSML SLC10 c.843C>G p.F281L YKYSRVADYIVKVSLWSLLVTLVVL[p.F2 LLVTLVVLL,LLIMTGTML,VLLIMTGTM,SLLVTLVVLL,LLV CESC A4 81L]LIMTGTMLGPELLASIPAAVYVIAIF TLVVLLI SLC10 c.326de|G p.G109fs YLLAISFSLKPVQAIAVLIMGCCPG[p.G1 LIMGCCPGA,GLMEIWISA,SLTFSPSGL,FSPSGLMEI,LTFSP STAD A6 09fs]APSLTFSPSGLMEIWISASV* SGLM,MEIWISASV,CPGAPSLTF,APSLTFSPS,SPSGLMEIW, VLIMGCCPGA,GLMEIWISAS,LMEIWISASV,SLTFSPSGLM, TFSPSGLMEI,MGCCPGAPSL,SPSGLMEIWI SLC10 c.782C>T p.S261L LILFIIFSIQLSFMLLTFIFSTRNN[p.S2 FIFSTRNNL,STRNNLGFT,RNNLGFTPA,FSTRNNLGF,NLGF UCEC A7 61L]LGFTPADTVAIIFCSTHKSLTLGIPM TPADTV,TFIFSTRNNL,IFSTRNNLGF SLC12 c.875C>T p.S292L ANAVAVAMYVVGFAETVVDLLKESD[p. LLKESDLMM,LLKESDLMMV,LMMVDPTNDI CRC A1 S292L]LMMVDPTNDIRIIGSITVVILLGI SV SLC12 c.2483G>A p.R828Q ALLHLVHDFTKNVGLMICGHVHMGP[p. MGPQRQAMK,HMGPQRQAM,PQRQAMKEM,HMGPQR UCEC A2 R828Q]QRQAMKEMSIDQAKYQRWLI QAMK,HVHMGPQRQA,GPQRQAMKEM,VHMGPQRQA KNKMKA M SLC12 c.2056de|C p.H686fs WGDGIRGLSLNAARYALLRVEHGPP[p. LRVEHGPPT,RVEHGPPTPR STAD A7 H686fs]TPRTGGPRCW* SLC13 c.1478_147 p.L493fs IVLLLGGGYALAKGSERSGLSEWLG[p.L SGLSEWLGK,SSHCHHPLP,HPLPPGGHL,KQADPTAEC,SSS KIRC A2 9insG 493fs]KQADPTAECASSSHCHHPLPPG HCHHPL,SEWLGKQAD,GLSEWLGKQA,RSGLSEWLGK,KQ GHLHRVH* ADPTAECA,ASSSHCHHPL,SEWLGKQADP,LPPGGHLHRV SLC13 c.818A>C p.Q273 VNFASWFAFAFPNMLVMLLFAWLWL[p. LLFAWLWLP,FAWLWLPFV,WLWLPFVYM,LFAWLWLPF, GBM A5 P Q273P]PFVYMRFNFKKSWGCGLESK AWLWLPFVY,WLPFVYMRF,PFVYMRFNF,LWLPFVYMR,F KNEKAA AWLWLPFVY,LLFAWLWLPF,LFAWLWLPFV,AWLWLPFV YM,LWLPFVYMRF,PFVYMRFNFK,WLWLPFVYMR,LPFVY MRFNF SLC16 c.1484G>A p.R495Q YDFSFYICGLLYMIGILFLLIQPCI[p.R495 LLIQPCIQI,CIQIIEQSR,FLLIQPCIQI,LLIQPCIQII, UCEC A14 Q]QIIEQSRRKYMDGAHV* QIIEQSRRKY,CIQIIEQSRR SLC16 c.293_294 p.G98fs LTFSAPLATVLSNRFGHRLVVMLGG[p. LLTRGFSYV,RLVVMLGGA,LTRGFSYVR,YVRRHRHHL,RHR STAD A6 insG G98fs]ATCQHRDGGRLLLTRGFSYVRR HHLWSG,LLLTRGFSY,GFSYVRRHR,CQHRDGGRL,GRLLLT HRHHLWSGILL* RGF,RGFSYVRRH,RHHLWSGIL,HHLWSGILL,LLLTRGFSYV, RLLLTRGFSY,SYVRRHRHHL,LTRGFSYVRR,RGFSYVRRHR, RHRHHLWSGI,MLGGATCQHR,ATCQHRDGGR,LLTRGFSY VR,VMLGGATCQH,CQHRDGGRLL,FSYVRRHRHH,YVRRH RHHLW,HRHHLWSGIL,RHHLWSGILL SLC16 c.1407_142 p.CVLL LGPPIVGWFYDWTQTYDIAFYFSGF[p. AFYFSGFFI,FYFSGFFIL,YFSGFFILL,IAFYFSGFF,IAFYFSG KIRC A9 4de|CTGCG GG470 CVLLGG470de|]FILLLAALPSWDTCNK FFI,AFYFSGFFIL,FYFSGFFILL,YFSGFFILLL,DIAFYFSGFF TCCTGCTG de| QLPKPAPTTFLYKVASNV* GGAGG SLC17 c.970G>A p.V324I HLINQGYRAITVRKLMQGMGLGLSS[p. GMGLGLSSI,GLSSIFALC,SIFALCLGH,MGLGLSSIF,LGLSSIF GBM A9 V324I]IFALCLGHTSSFCESVVFASASIGLQ AL,LSSIFALCL,GLGLSSIFAL,GLSSIFALCL,GMGLGLSSIF,QG MGLGLSSI SLC1A2 c.1044_1045 p.F348fs LIIFIGGIFLPLIYFVVTRKNPFSFF[p.F348 KNPFSFFCW,PFSFFCWHF,SFFCWHFPS,FFCWHFPSL,LDH LUAD insT fs]CWHFPSLDHCPGHRFQCWNFACHL CPGHRF,GHRFQCWNF,FQCWNFACH,WNFACHLSL,NPFS SLPGRKSGD* FFCWH,FPSLDHCPG,CPGHRFQCW,SFFCWHFPSL,FQCW NFACHL,CWNFACHLSL,FACHLSLPGR,FSFFCWHFPS,RKN PFSFFCW,NPFSFFCWHF,SLDHCPGHRF,FPSLDHCPGH SLC20 c.984_985 p.P328fs PLQAVVEERTVSFKLGDLEEAPERE[p.P LEEAPEREA,RGLERGNQHR UCEC A1 de|AG 328fs]ASQRGLERGNQHR* SLC22 c.602C>T p.S201L NGGMSLVAFVLLNECVGTAYWALAG[p. ALAGLIGGL,GLIGGLFFA,LIGGLFFAV,TAYWALAGL,AYWA CRC A15 S201L]LIGGLFFAVGIAQYALLGYFIRS LAGLI,LAGLIGGLF,AGLIGGLFF,GLIGGLFFAV,GTAYWALA WRT GL,ALAGLIGGLF,TAYWALAGLI,LAGLIGGLFF SLC22 c.1220G>A p.R407Q LQTLFGAVILLANCVAPWALKYMNR[p. YMNRQASQM,ALKYMNRQA,KYMNRQASQ,RQASQMLL GBM A9 R407Q]QASQMLLMFLLAICLLAIIFVPQ M,MNRQASQML,QASQMLLMF,LKYMNRQAS,YMNRQA EMQ SQML,KYMNRQASQM,RQASQMLLMF,MNRQASQMLL,L KYMNRQASQ,NRQASQMLLM SLC24 c.401C>T p.A134V SENSTDHAQGDYPKDIFSLEERRKG[p.A RKGVIILHV,VIILHVIGMI,SLEERRKGVI,RKGVIILHVI, CRC A2 134V]VIILHVIGMIYMFIALAIVCDEFFVP EERRKGVIIL SLC24 c.103C>A p.R35S ARRALLLGILWATAHLPLSGTSLPQ[p.R SLPQSLPRA,TSLPQSLPR,LPQSLPRAT,GTSLPQSLPR LUAD A5 35S]SLPRATGNSTQCVISPSSEFPEGFFT SLC25 c.84de|T p.F28fs LSYESLVHAVAGAVGSVTAMTVFFP[p. AMTVFFPWI,IQLDFDFRL,RLMRKENPK,KLHTWCSWR,CS STAD A17 F28fs]WIQLDFDFRLMRKENPKLHTWC WRSLKKK,TWCSWRSLK,TAMTVFFPW,FFPWIQLDF,PWI SWRSLKKKDSWHHIEGGFQ* QLDFDF,SWHHIEGGF,LMRKENPKL,HTWCSWRSL,WIQL DFDFR,DFDFRLMRK,TVFFPWIQL,KENPKLHTW,RSLKKKD SW,KKKDSWHHI,RLMRKENPKL,HTWCSWRSLK,TWCSW RSLKK,VTAMTVFFPW,TAMTVFFPWI,VFFPWIQLDF,LMR KENPKLH,MTVFFPWIQL,IQLDFDFRLM,RKENPKLHTW,L HTWCSWRSL,LKKKDSWHHI,FPWIQLDFDF,NPKLHTWCSW SLC25 c.247C>G p.Q83E LRPKYNGILHCLTTIWKLDGLRGLY[p.Q GLYEGVTPN,GLRGLYEGV,LYEGVTPNI,YEGVTPNIW,GLYE BRCA A32 83E]EGVTPNIWGAGLSWGLYFFFYNAI GVTPNI,LYEGVTPNIW KS SLC25 c.287G>A p.R96Q EGGNKLWYKKPGNFQGTLDAFFKII[p. IQNEGIKSL,KIIQNEGIK,FKIIQNEGI,IQNEGIKSLW CRC A40 R96Q]QNEGIKSLWSGLPPTLVMAVPA TVIY SLC25 c.316G>T p.G106C LLVLTATSHQERRAQPPSYMHIFLA[p.G FLACCTGGF,YMHIFLACC,SYMHIFLAC,YMHIFLACCT,FLA BRCA A45 106C]CCTGGFLQAYCLAPFDLIKVRLQN CCTGGFL,SYMHIFLACC,IFLACCTGGF,CCTGGFLQAY QT SLC25 c.199G>A p.A67T TLSCIRVVYRRESMFGFFKGMSFPL[p.A GMSFPLTSI,TSIAVYNSV,MSFPLTSIA,FPLTSIAVY,MSFPLT DLBCL A48 67T]TSIAVYNSVVFGVFSNTQRFLSQH SIAV,GMSFPLTSIA,LTSIAVYNSV,KGMSFPLTSI,SFPLTSIAV RC Y,SIAVYNSVV SLC25 c.301C>A p.R101S VFGVFSNTQRFLSQHRCGEPEASPP[p. SPPSTLSDL,EPEASPPSTL LUAD A48 R101S]STLSDLLLASMVAGVVSVGLGG PVDL SLC25 c.235A>T p.I79F IIDCVVRIPKEQGVLSFWRGNLANV[p.I NLANVFRYF,RGNLANVFR,VFRYFPTQA,GNLANVFR,WR CESC A5 79F]FRYFPTQALNFAFKDKYKQIFLGGV GNLANVF,FRYFPTQAL,NVFRYFPTQA,FWRGNLANVF,VF D RYFPTQAL,RGNLANVFRY,GNLANVFRYF SLC25 c.352G>A p.A118T DKYKQIFLGGVDKRTQFWLYFAGNL[p. WLYFAGNLT,LTSGGAAGA,NLTSGGAAGA,WLYFAGNLTS KIRC A5 A118T]TSGGAAGATSLCFVYPLDFART RLAA SLC26 c.262G>A p.V88I WLPAYRLKEWLLSDIVSGISTGIVA[p.V GISTGIVAI,GIVAILQGL,AILQGLAFA,ILQGLAFAL,VAILQGL GBM A3 88I]ILQGLAFALLVDIPPVYGLYASFFPA AF,ISTGIVAIL,AILQGLAFAL,ILQGLAFALL,GISTGIVAIL, GIVAILQGLA,IVAILQGLAF,SGISTGIVAI SLC26 c.1886de|T p.I629fs LAHCTASLIKAMTYYGNLDSEKPIF[p.I6 KPIFLNRYL,NLDSEKPIFL,SEKPIFLNRY,DSEKPIFLNR, STAD A7 29fs]LNRYLLQ* KPIFLNRYLL SLC27 c.1927de|C p.P643fs VNVYGVTVPGHEGRAGMAALVLRPP[p. WQMRASTPA,ALVLRPPTL,CSSTPTCLR,LTHCTFWTR,GSR STAD A3 P643fs]TLWTLCSSTPTCLRTCHLM SLWPPQ,PQRPSNSRK,QMRASTPAP,RASTPAPCL,NSRKF PGPDSSGSRSLWPPQRPSNSRKFGWQ GWQM,LVLRPPTLW,RKFGWQMRA,APCLTHCTF,VLRPPT MRASTPAPCLTHCTFWTRL* LWTL,TLCSSTPTCL,GSRSLWPPQR,RSLWPPQRPS,NSRKF GWQMR,QMRASTPAPC,LTHCTFWTRL,CLTHCTFWTR,TP TCLRTCHL,GPDSSGSRSL,AALVLRPPTL,ALVLRPPTLW,PQ RPSNSRKF,SNSRKFGWQM,RKFGWQMRAS,WQMRASTP AP,MRASTPAPCL,RPSNSRKFGW,APCLTHCTFW SLC2A6 c.689C>A p.A230D LIMILLLSFMPNSPRFLLSRGRDEE[p.A2 DLRALAWLR,EEDLRALAW,DEEDLRALAW,EEDLRALAWL PRAD 30D]DLRALAWLRGTDVDVHWEFEQI QDNV SLC2A7 c.193G>A p.A65T YNLSVVNTPHKVFKSFYNETYFERH[p.A TYFERHTTF,ETYFERHTT,HTTFMDGKL,YFERHTTFM,TTF CRC 65T]TTFMDGKLMLLLWSCTVSMFPLG MDGKLM,TYFERHTTFM,ETYFERHTTF GLL SLC2A7 c.804C>A p.H268Q LRGHTDMEAELEDMRAEARAERAEG[p. RAEGQLSVL,AERAEGQLS,AEGQLSVLH,QLSVLHLCAL,AER TGCT H268Q]QLSVLHLCALRSLRWQLLSIIV AEGQLSV,AEGQLSVLHL,GQLSVLHLCA LMAG SLC30 c.581G>A p.R194H LRSDVEAKSLEVWGSPEALAREKKL[p.R LAREKKLHK,LHKEAEIEY,REKKLHKEA,ALAREKKLHK,KLHK CRC A9 194H]HKEAEIEYRERLFRNQKILREYRD EAEIEY FL SLC32 c.1480G>A p.V494I CFLLPSLFHLRLLWRKLLWHQVFFD[p.V VFFDIAIFV,LWHQVFFDI,FFDIAIFVI,IAIFVIGGI,QVFFDI STAD A1 494I]IAIFVIGGICSVSGFVHSLEGLIEAY AIF,HQVFFDIAI,LLWHQVFFDI,QVFFDIAIFV,VFFDIAIFVI, DIAIFVIGGI,HQVFFDIAIF,WHQVFFDIAI SLC33 c.1625C>T p.S542L CVFIGFGWWFFLGPKFKKLQDEGSS[p. KLQDEGSSL,LQDEGSSLW,KKLQDEGSSL,KLQDEGSSLW CRC A1 S542L]LWKCKRNN* SLC35 c.1250G>C p.*417S VWRLVRGTRYMKKDYLIENEELPSP[p. PSEGGACTY,CTYLCAYTY,YLCAYTYFI,TYLCAYTYF,GACTYL HNSC D3 *417S]SEGGACTYLCAYTYFIC* CAY,SEGGACTYL,YLCAYTYFIC,CTYLCAYTYF,TYLCAYTYFI, GGACTYLCAY,ACTYLCAYTY,SPSEGGACTY SLC35 c.838G>A p.A280T CNKAFVFLLSWIVLRDRFMGVRIVA[p. FMGVRIVAT,RIVATILAI,IVATILAIA,ATILAIAGI,GVRIVATIL, CRC F3 A280T]TILAIAGIVMMTYADGFHSHSVI TILAIAGIV,MGVRIVATI,FMGVRIVATI,RIVATILAIA,ATILAI GIA AGIV,RFMGVRIVAT,GVRIVATILA,MGVRIVATIL,VRIVATIL AI,TILAIAGIVM SLC35 c.184de|A p.K62fs INEGYGNFMEENPKKGLLSEMKKKG[p. LSLEPWIPY,SLEPWIPYL,SEMKKKGEL,MKKKGELSL,GELSL CESC G2 K62fs]ELSLEPWIPYLHQQKTQ* EPWI,IPYLHQQKT,LSLEPWIPYL,EMKKKGELSL,ELSLEPWI PY,KKGELSLEPW SLC37 c.1582G>A p.V528I ACALLFLIRLIHKELSCPGSATGDQ[p.V5 ATGDQIPFK,SATGDQIPF,SATGDQIPFK,GSATGDQIPF,CP TGCT A1 28I]IPFKEQ* GSATGDQI SLC38 c.298G>A p.G100R MSVFNLSNAIMGSGILGLAFALANT[p. ALANTRILL,RILLFLVLL,LAFALANTR,NTRILLFLV,LANTRILL TGCT A1 G100R]RILLFLVLLTSVTLLSIYSINLLLIC F,FALANTRIL,TRILLFLVL,ALANTRILLF,NTRILLFLVL,GLAFA LANTR,LAFALANTRI,FALANTRILL SLC38 c.3213_321 p.1071_107 SDLRRRRRDLGPHAEGQLAPRDGVI[p. APRDGVIGL,RDGVIGLNPL PAAD A10 5de|CAT 2II>I 1071_1072II>I]GLNPLPDVQVNDLRG ALDAQLRQAAGGA SLC39 c.1883G>C p.C628S ILMNFISSLTAFMGLYIGLSVSADP[p.C6 SVQDWIFTV,DPSVQDWIF,GLSVSADPSV LUAD A12 28S]SVQDWIFTVTAGMFLYLSLVEMLP EM SLC39 c.158G>T p.R53L AFPQTTEKISPNWESGINVDLAIST[p.R TLQYHLQQL,AISTLQYHL,LQYHLQQLF,DLAISTLQY,LQYHL LUAD A6 53L]LQYHLQQLFYRYGENNSLSVEGFR QQLFY,TLQYHLQQLF,INVDLAISTL,VDLAISTLQY,LAISTLQ KL YHL,STLQYHLQQL SLC39 c.1144C>T p.R382C LHEVPHEVGDFAILVQSGCSKKQAM[p. KQAMCLQLL,AMCLQLLTA,KKQAMCLQL,AMCLQLLTAV,S CRC A7 R382C]CLQLLTAVGALAGTACALLTEG KKQAMCLQL,KKQAMCLQLL,KQAMCLQLLT GAVG SLC39 c.1367_136 p.L456fs SVLPELLREASPLQSLLEVLGLLGG[p.L4 VLGLLGGSY,LLGGSYHDGA,EVLGLLGGSY,LEVLGLLGGS CLL A7 8insG 56fs]SYHDGADCPP* SLC43A1 c.398C>T p.P133L LVGSACFTASCTLMALASRDVEALS[p.P ALSLLIFLA,LLIFLALSL,EALSLLIFL,RDVEALSLL,VEALSL CRC 133L]LLIFLALSLNGFGGICLTFTSLTLPN LIF,LSLLIFLAL,ALSLLIFLAL,SLLIFLALSL,ASRDVEALSL, EALSLLIFLA,RDVEALSLLI,VEALSLLIFL SLC43A3 c.647G>A p.R216H LLYEKGISLRASFIFISVCSTWHVA[p.R21 STWHVAHTF,TWHVAHTFL,HVAHTFLLM,WHVAHTFLL,S CRC 6H]HTFLLMPRGHIPYPLPPNYSYGLCP TWHVAHTFL,VAHTFLLMPR,CSTWHVAHTF,TWHVAHTFL G L,WHVAHTFLLM SLC44A5 c.208G>T p.V70F KPADTPSEEEDFGDPRTYDPDFKGP[p. FANRSCTDV,DFKGPFANR,TYDPDFKGPF,FANRSCTDVL KIRC V70F]FANRSCTDVLCCMIFLLCIIGYIVL G SLC44A5 c.554G>A p.R185H CPEKFLTYVEMQLLYTKDKSYWEDY[p. HQFCKTTAK,SYWEDYHQF,YHQFCKTTA,KSYWEDYH CRC R185H]HQFCKTTAKPVKSLTQLLLDDD QF,SYWEDYHQFC,HQFCKTTAKP,WEDYHQFCKT CPTA SLC4A3 c.3183de|G p.L1061fs SQKARRLLKGSGFHLDLLLIGSLGG[p.L1 LLIGSLGGS,LIGSLGGSV,SLGGSVGCL,RSAPSPMSM,SAPS STAD 061fs]SVGCLGCPGSRLPRSAPSPMSM PMSMR,LPRSAPSPM,LLIGSLGGSV,RLPRSAPSPM,RSAPSPMS R* MR,GSRLPRSAPS SLC4A5 c.1597A>G p.I533V WFPSDFYDGFHIQSISAILFIYLGC[p.I53 ILFIYLGCV,YLGCVTNAI,GCVTNAITF,AILFIYLGCV,FIYLGCV LUAD 3V]VTNAITFGGLLGDATDNYQGVMES TNA,YLGCVTNAIT,ILFIYLGCVT,IYLGCVTNAI,LGCVTNAITF FL SLC4A8 c.687C>G p.N229K LNDSMRVKVREALLKKHHHQNEKKR[p. KKRKNLIPI,KRKNLIPIV,KKRKNLIPIV,EKKRKNLIPI,HQNEK KIRC N229K]KNLIPIVRSFAEVGKKQSDPHL KRKNL,KNLIPIVRSF MDKH SLC52A1 c.1108_111 p.G370de| LSLLGMLFGAYLMALAILSPCPPLV[p.G VTTAGVVLV,LVTTAGVVL,LVTTAGVVLV,VTTAGVVLVV,C KIRC 0de|GGC 370de|]TTAGVVLVVLSWVLCLCVFSYV PPLVTTAGV KVAASS SLC52A2 c.1197_1198 p.G399fs LSWVLCLGVFSYVKVAASSLLHGGG[p. SLLHGGGPA,LSARRCCYV,HLSRVPQQK,CYVPPDQHL,GSR KIRC insG G399fs]PAGIAGSRRGHPGGLSARRCC RGHPGG,RGHPGGLSA,GLSARRCCY,QQKGLCRPL,LLHGG YVPPDQHLSRVPQQKGLCRPL* GPAGI,GLSARRCCYV,GSRRGHPGGL,RGHPGGLSAR,SARR CCYVPP,VPPDQHLSRV SLC5A1 c.157G>T p.G53W DISIIVIYFVVVMAVGLWAMFSTNR[p. WTVGGFFLA,WAMFSTNRW,MFSTNRWTV,RWTVGGFFL, LUAD G53W]WTVGGFFLAGRSMVWWPIGA AMFSTNRWT,TNRWTVGGF,NRWTVGGFF,AMFSTNRW SLFASN TV,LWAMFSTNRW,RWTVGGFFLA,STNRWTVGGF,TNR WTVGGFF SLC5A7 c.1006G>T p.G336C KTTEEADMILPIVLQYLCPVYISFF[p.G3 YISFFCLGA,CLGAVSAAV,ISFFCLGAV,VYISFFCLG,YISFFCL HNSC 36C]CLGAVSAAVMSSADSSILSASSMF GAV,FCLGAVSAAV,VYISFFCLGA,CLGAVSAAVM,CPVYISF AR FCL SLC5A7 c.1325G>T p.G442V IFPQLLCVLFVKGTNTYGAVAGYVS[p.G AVAGYVSVL,YVSVLFLRI,VAGYVSVLF,GYVSVLFLR,AGYVS LUAD 442V]VLFLRITGGEPYLYLQPLIFYPGYY VLFL,AGYVSVLFLR,AVAGYVSVLF,GYVSVLFLRI,YGAVAGY P VSV,GAVAGYVSVL SLC6A10P c.264A>C p.K88N WSFFTPLVCMGIFIFNVVYYKPLVY[p.K YYKPLVYNN,YYKPLVYNNT,KPLVYNNTNV GBM,KIRC 88N]NNTNVYPWWGEAMGWAFVLSS MLCMP SLC6A11 c.896G>T p.W299L TLPGASEGIKFYLYPDLSRLSDPQV[p.W RLSDPQVLV,VLVDAGTQI,SRLSDPQVL,LVDAGTQIF,LVDA LUAD 299L]LVDAGTQIFFSYAICLGCLT GTQIFF,VLVDAGTQIF,LSRLSDPQVL ALGSYN SLC6A14 c.255_256 p.A85fs FPYLTYSNGGGAFLIPYAIMLALAG[p. LALAGFTFV,ALAGFTFVL,VLSGVFTGT,MLALAGFTF,FTFVL KIRC insG A85fs]FTFVLSGVFTGTIC* SGVF,AIMLALAGF,MLALAGFTFV,FVLSGVFTGT,VLSGVFT GTI,AIMLALAGF,ALAGFTFVLS,AGFTFVLSGV,YAIMLALA GFT,IMLALAGFTF,GFTFVLSGVF,FTFVLSGVF,LALAGFTFVL SLC6A9 c.281G>A p.R94K LLPQLMAQHSLAMAQNGAVPSEATK[p. AVPSEATKK,ATKKDQNLK,ATKKDQNLKR CLL R94K]KDQNLKRGNWGNQIEFVLTSV GYAVG SLC6A9 c.727C>T p.R243W AYCNNPWNTHDCAGVLDASNLTNGS[p. NLTNGSWPA,WPAALPSNL,ASNLTNGSW,NLTNGSWPAA, BLCA R243W]WPAALPSNLSHLLNHSLQRT SWPAALPSNL,LTNGSWPAAL,DASNLTNGSW SPSEEY SLC7A10 c.471de|C p.P157fs TSLAVISMTFSNYVLQPVFPNCIPP[p. FPNCIPPPQ STAD P157fs]PQPPGCCPWPA* SLC7A2 c.964C>T p.R322W TLAGAATCFYAFVGFDCIATTGEEV[p.R EVWNPQKAI,EEVWNPQKA,IATTGEEVW,EEVWNPQKAI, UCEC 322W]WNPQKAIPIGIVTSLLVCFMAYF GEEVWNPQKA GVS SLC8A1 c.1292G>A p.R431H VSKIFFEQGTYQCLENCGTVALTII[p. GTVALTIIH,TVALTIIH,GTVALTIIHR CRC R431H]HRGGDLTNTVFVDFRTEDGTANA GSD SLC8A1 c.1297G>T p.G433C KIFFEQGTYQCLENCGTVALTIIRR[p.G4 CGDLTNTVF,RCGDLTNTVF LUAD 33C]CGDLTNTVFVDFRTEDGTANAGS DYE SLC9A2 c.2237de|C p.T746fs SPQSYKMEWKNEVDVDSGRDMPSTP[p. SLAQRGKTV,KTSLAQRGK,RQAYYSSPF,AYYSSPFSL,RAPR STAD T746fs]QHPTAEKRAPRRQAYYSSPF RQAYY,YYSSPFSLK,SLKTSLAQR,KRAPRRQAY,PTAEKRAP SLKTSLAQRGKTV* R,MPSTPQHPT,SPFSLKTSL,AYYSSPFSLK,STPQHPTAEK,FS LKTSLAQR,RQAYYSSPFS,QAYYSSPFSL,KRAPRRQAYY,PT AEKRAPRR,MPSTPQHPTA,SPFSLKTSLA,RRQAYYSSPF,AE KRAPRRQA SLC9A4 c.1892G>A p.R631H RTLSYNKYNLKPQTSEKQAKEILIR[p.R6 ILIRHQNTL,LIRHQNTLR,HQNTLRESM,KEILIRHQN,ILIRH GBM 31H]HQNTLRESMRKGHSLPWGKPAG QNTLR,HQNTLRESMR,EILIRHQNTL,KQAKEILIRH,RHQNT TKNI LRESM,KEILIRHQNT SLC9A5 c.1341G>C p.L447F TKVPAKDYFVATTIWVFFTVIVQG[p.L4 VIVQGFTIK,FFTVIVQGF,FTIKPLVKW,GFTIKPLVK,FTVIVQGFT, BLCA 47F]FTIKPLVKWLKVKRSEHHKPTLNQE TVIVQGFTI,VQGFTIKPL,FTIKPLVKWL,TVIVQGFTIK,QGFTIK L PLVK,VFFTVIVQGF,GFTIKPLVKW,FTVIVQGFTI SLC9B1 c.1338_1339 p.V446fs FAGFSFKEKIFIALAWMPKATVQAV[p. HSSKWSSTY,SLRTPLGTI,RSSGSRNSK,FSHLDHSSK,GSRNSKS KIRC de|GT V446fs]RSSGSRNSKSLRTPLGTICEGCD LR,SSKWSSTYG,NSKSLRTPL,SHLDHSSKW,SKWSSTYG DSSIFSHLDHSSKWSSTYGHSGA* H,AVRSSGSRNS,KSLRTPLGTI,IFSHLDHSSK,SSKWSSTYGH, MPKATVQAVR,RNSKSLRTPL,CEGCDDSSIF,FSHLDHSSKW SLCO2A1 c.1437G>C p.M479I IFHPVCGDNGIEYLSPCHAGCSNIN[p.M ISSATSKQL,NINISSATSK,ISSATSKQLI CESC 479I]ISSATSKQLIYLNCSCVTGGSASAKT SLIT1 c.4379G>T p.R1460L SGTKGAHCVCDPGFSGELCEQESEC[p. ESECLGDPV,CLGDPVRDF,QESECLGDPV LUAD R1460L]LGDPVRDFHQVQRGYAICQTT RPLSW SLITRK1 c.134de|A p.K45fs TGDVCKEKICSCNEIEGDLHVDCEK[p.K FTIYFCMAI,SLMSSLTFI,LMSSLTFIM,SLTFIMRLV,IMRLVC STAD 45fs]RASQVCSVSLPRLPSFTIYFCMAIP TWK,TMACMKSFR,QVCSVSLPR,MSSLTFIMR,VSLPRLPSF, SLDFSLMSSLTFIMRLVCTWKTMACMK RLPSFTIYF,YFCMAIPSL,CMAIPSLDF,FSLMSSLTF,FIMRLV SFRGLFWGCSW* CTW,KTMACMKSF,CMKSFRGLF,RGLFWGCSW,TWKTM ACMK,KSFRGLFWG,LPRLPSFTI,IPSLDFSLM,RLVCTWKT M,KRASQVCSV,ASQVCSVSL,SQVCSVSLP,LDFSLMSSL,CT WKTMACM,MKSFRGLFW,CEKRASQVC,LPSFTIYFC,SLPR LPSFTI,RLPSFTIYFC,SLDFSLMSSL,FSLMSSLTFL,SLMSSLTFI M,RLVCTWKTMA,LMSSLTFIMR,FIMRLVCTWK,CTWKTM ACMK,KTMACMKSFR,SQVCSVSLPR,SFTIYFCMAI,IYFCM AIPSL,FCMAIPSLDF,DFSLMSSLTF,TFIMRLVCTW,CMKSF RGLFW,SSLTFIMRLV,MAIPSLDFSL,MSSLTFIMRL,RASQV CSVSL,LPRLPSFTIY,LPSFTIYFCM,MACMKSFRGL,SVSLPRL PSF,MRLVCTWKTM,WKTMACMKSF,ACMKSFRGLF,FRGL FWGCSW,CEKRASQVCS SLITRK1 c.155G>A p.R52H KICSCNEIEGDLHVDCEKKGFTSLQ[p.R SLQHFTAPT,KGFTSLQHF,HFTAPTSQF,FTSLQHFTA, CRC 52H]HFTAPTSQFYHLFLHGNSLTRLFPN LQHFTAPTS,HFTAPTSQFY,KKGFTSLQHF,LQHFTA E PTSQ,QHFTAPTSQF SLITRK3 c.641G>T p.R214L PTNLFKAVSLTHLDLRGNRLKVLFY[p.R FYLGMLDHI,RLKVLFYLG,KVLFYLGML,LKVLFYLG LUSC 214L]LGMLDHIGRSLMELQLEENPWN M,LFYLGMLDHI,RLKVLFYLGM,YLGMLDHIGR, CTCE LKVLFYLGML SLITRK3 c.893C>T p.S298L REIRKTELCPLLSDSEVEASLGIPH[p.S29 GIPHLSSSK,LSSSKENAW,LGIPHLSSSK,VEASLGIPHL,HLSS CRC 8L]LSSSKENAWPTKPSSMLSSVH SKENAW FTASS SLITRK5 c.1403G>T p.R468M NRISMIQDRAFGDLTNLRRLYLNGN[p. RLYLNGNMI,YLNGNMIER,RRLYLNGNM,YLNGNMIERL,N LUAD R468M]MIERLSPELFYGLQSLQYLFLQY MIERLSPEL,LYLNGNMIER,LRRLYLNGNM,RRLYLNGNMI, NLI MIERLSPELF SLITRK5 c.203G>T p.R68L YYGEICDNACPCEEKDGILTVSCEN[p.R ILTVSCENL,TVSCENLGI,CENLGIISL,NLGIISLSEI,LTVSCENL LUAD 68L]LGIISLSEISPPRFPIYHLLLSGNLL GI,CENLGIISLS SLITRK6 c.2223C>A p.N741K HLQRSLLEQENHSPLTGSNMKYKTT[p. KQSTEFLSF,SNMKYKTTK,KYKTTKQST,TTKQSTEFL,KTTKQ LUAD N741K]KQSTEFLSFQDASSLYRNILEKE STEF,GSNMKYKTTK,KTTKQSTEFL,MKYKTTKQST,YKTTKQ REL STEF,TKQSTEFLSF SMAD2 c.962G>A p.R321Q SLTVDGFTDPSNSERFCLGLLSNVN[p.R LLSNVNQNA,VNQNATVEM,GLLSNVNQNA,NVNQNATVEM CRC 321Q]QNATVEMTRRHIGRGVRLYYIG GEVF SMAD4 c.1082G>A p.R361H GETFKVPSSCPIVTVDGYVDPSGGD[p.R YVDPSGGDHF,DPSGGDHFCL CRC 361H]HFCLGQLSNVHRTEAIERARLHIG KG SMAP1 c.506de|A p.E169fs QPLVSSPSLQAAVDKNKLEKEKEKK[p.E ALKKLRSPL,KISNWSLKK,SLKKVPALK,KLRSPLWIF,KKRKRK UCS 169fs]RKRKREKRSQKSRQNHLQLKSCR REK,RKREKRSQK,RSQKSRQNH,SQKSRQNHL,KSRQNHLQ RKISNWSLKKVPALKKLRSPLWIF* L,RRKISNWSL,RKISNWSLK,KVPALKKLR,HLQLKSCRR,WSL KKVPAL,RQNHLQLKS,KKVPALKKL,LKKLRSPLW,KKLRSPL WI,KISNWSLKKV,KSRQNHLQLK,SLKKVPALKK,WSLKKVP ALK,KRKREKRSQK,RSQKSRQNFIL,HLQLKSCRRK,RRKISN WSLK,CRRKISNWSL,NWSLKKVPAL,QKSRQNHLQL,RQNH LQLKSC,LQLKSCRRKI,ALKKLRSPLW,KKLRSPLWIF SMARCA4 c.1142G>A p.R381Q QKPRGLDPVEILQEREYRLQARIAH[p.R LQARIAHQI,RIAHQIQEL,HQIQELENL,RLQARIAHQI, CRC 381Q]QIQELENLPGSLAGDLRTKATIEL ARIAHQIQEL KA SMARCA4 c.2738C>T p.P913L NHHCKLTQVLNTHYVAPRRLLLTGT[p. RLLLTGTLL,LLQNKLPEL,LTGTLLQNK,RRLLLTGTL, HNSC P913L]LLQNKLPELWALLNFLLPTIFKSC TLLQNKLPEL,LLTGTLLQNK,RRLLLTGTLL ST SMARCA5 c.468_471 p.T156fs KQNLLSVGDYRHRRTEQEEDEELLT[p.T APKQPMFAL,LLTAPKQPM,LTAPKQPMF,KQPMFALDL,LD TGCT de|AGAA 156fs]APKQPMFALDLKTLHRM* LKTLHRM,KQPMFALDLK,LTAPKQPMFA,FALDLKTLHR,TA PKQPMFAL,LLTAPKQPMF,PMFALDLKTL,QEEDEELLTA SMC3 c.2908G>C p.E970Q ELGSLPQEAFEKYQTLSLKQLFRKL[p.E9 KLQQCNTEL,KLQQCNTELK,QQCNTELKKY,RKLQQCNTEL TGCT 70Q]QQCNTELKKYSHVNKKALDQFVN FSE SMCR8 c.523G>A p.E175K VRPFCMAYISADQHKIMQQFQELSA[p. ELSAKFSRA,QQFQELSAK,QFQELSAKF,AKFSRASEC,MQQ UCEC E175K]KFSRASECLKTGNRKAFAGELEK FQELSAK,KFSRASECLK,QQFQELSAKF,AKFSRASECL,QELS KLK AKFSRA SMG1 c.8087C>A p.P2696H LICNTTVERCQELYRKYEMQYAPQP[p. YAPQPHPTV,APQPHPTVC,QPHPTVCQF,MQYAPQPHP,Q TGCT P2696H]HPTVCQFITATEMTLQRYAAD YAPQPHPTV,YEMQYAPQPH,MQYAPQPHPT,HPTVCQFIT INSRL A,QPHPTVCQFI SMG7 c.2536_2537 p.E846fs TQDPIKLFEPSLQPPVMQQQPLEKK[p. NEAFSHGAI,QPLEKKNEAF,KKNEAFSHGA PRAD insA E846fs]NEAFSHGAI* SNAPC1 c.633de|T p.D211fs QNMKHVISVDKSKPDKALSLIKDDF[p. LIKDDFLTI,IKDDFLTIL,SLIKDDFLTI,ALSLIKDDFL, STAD D211fs]LTILRT* LIKDDFLTIL SNAPC2 c.875de|C p.T292fs IPAGGSLGPAAEGDGAGSKAPEETP[p. TPQPPRRPS,TPQPPRRPST STAD T292fs]QPPRRPSTAN* SND1 c.112C>G p.Q38E GPAVPTVQRGIIKMVLSGCAIIVRG[p.Q AIIVRGEPR,CAIIVRGEPR CESC 38E]EPRGGPPPERQINLSNIRAGNLAR RA SND1 c.2163de|C p.H721fs VQDVETGTQLEKLMENMRNDIASHP[p. RNDIASHPL,MRNDIASHPL STAD H721fs]L* SOAT1 c.190de|T p.F64fs GRIDIKQLIAKKIKLTAEAEELKPF[p. AEAEELKPFL STAD F64fs]L* SOLH c.2141G>A p.R714H GFLMGASCGGGNMKVDDSAYESLGL[p.R71 GLHPRHAYS,LGLHPRHAY,HPRHAYSIL,SAYESLGLH,YESL LIHC 4H]HPRHAYSILDVRDVQGTRLLRLRNPW GLHPR,GLHPRHAYSI,SLGLHPRHAY,YESLGLHPRH SON c.2723C>T p.S908L AQMLASGTMDAQMLASSTQDSAMLG GLKSPDPYR,LGLKSPDPY,TQDSAMLGL,LKSPDPYRL,GLKS LUSC [p.S908L]LKSPDPYRLAQDPYRLAQDP PDPYRL,TQDSAMLGLK,MLGLKSPDPY,STQDSAMLGL YRLGHD SON c.4075_409 p.VLES LAESILEPPAMAAPESSAMAVLESS[p.V AMAVLESST,MAVLESSTV,AMAVLESSTV,AVLESSTVTV KIRC 8de|GTCCT SAVT13 LESSAVT1359de|]TVTVLESSTVTVLEP GGAGTCTT 59de| SVVTVPEPPVVAEPDYVTIPVPVVSALE CGGCTGTG PSVPVL ACC SORBS1 c.1710C>A p.F570L VLTNEKMSRDISPEEIDLKNEPWYK[p.F KNEPWYKLF,PWYKLFSEL,LKNEPWYKL,YKLFSELEF,KLFSE CRC 570L]LFSELEFGKPPPKKIWDYTPGDCSIL LEFGK,WYKLFSELEF,EPWYKLFSEL,LKNEPWYKLF SORBS1 c.3466G>A p.V1156M AERGAGERGPGGPKISKKSCLKPSD[p.V CLKPSDMVR,KPSDMVRCL,MVRCLSTEQR,KKSCLKPSDM CRC 1156M]MVRCLSTEQRLSDLNTPEESRP GKPL SORBS2 c.2596C>T p.P866S VFEALDSALKDICDQIKAEKKRGSL[p.P8 RGSLSDNSI,LSDNSILHRL,SLSDNSILHR,RGSLSDNSIL PAAD 66S]SDNSILHRLISELLPDVPERNSSLRA SORBS2 c.3472 p.E1158fs DRIHSLSSNKPQRPVFTHENIQGGG[p.E SSEKVMSLM,KMSWSSEKV,SLMSWKSVM,LMSWKSVMT, STAD de|G 1158fs]NRFRLCITILPGMKMSWSSEKV KVMSLMSWK,CITILPGMK,RFRLCITIL,ILPGMKMSW,MS MSLMSWKSVMTAGLWGPQEEPNSLV LMSWKSV,MSWKSVMTA,TTSRGCELR,MTAGLWGPQ,ET LSPETTSRGCELRSLLL* TSRGCEL,GPQEEPNSL,MSWSSEKVM,NRFRLCITI,ITILPG MKM,WSSEKVMSL,EKVMSLMSW,WKSVMTAGL,KSVMT AGLW,QEEPNSLVL,SEKVMSLMS,VMSLMSWKSV,SLMS WKSVMT,LMSWKSVMTA,RLCITILPGM,GMKMSWSSEK, LVLSPETTSR,RFRLCITILP,MSLMSWKSVM,SWKSVMTAGL, NIQGGGNRFR,ETTSRGCELR,WSSEKVMSLM,KMSWSSE KVM,IQGGGNRFRL,NRFRLCITIL,MKMSWSSEKV,SEKVM SLMSW,MSWKSVMTAG,WKSVMTAGLW SORCS2 c.958C>T p.R320W FWSVSGVDADPDLVHVEAQDLGGDF[p. DLGGDFWYV,DFWYVTCAI,GDFWYVTCA,AQDLGGDFWY, CRC R320W]WYVTCAIHNCSEKMLTAPF GDFWYVTCAI,EAQDLGGDFW AGPIDHG SORL1 c.614G>T p.R205L ADAYAQYLWITFDFCNTLQGFSIPF[p.R LQGFSIPFL,PFLAADLLL,IPFLAADLL,TLQGFSIPFL,FLAADLL LUAD 205L]LAADLLLHSKASNLLLGFDRSHPN LHS,LAADLLLHSK,FSIPFLAADL,IPFLAADLLL KQ SOS1 c.697A>T p.N233Y FMAEIRQYIRELNLIIKVFREPFVS[p.N23 PFVSYSKLF,VFREPFVSY,VSYSKLFSA,EPFVSYSKL,REPFVSY LUAD,UCEC 3Y]YSKLFSANDVENIFSRIVDIHELSVK SK,FVSYSKLFSA,KVFREPFVSY,VFREPFVSYS,REPFVSYSKL, EPFVSYSKLF SOWAHA c.371G>C p.R124P AAQPSKPTSTVLPRSASAPGAPPLV[p.R APGAPPLVPV ACC 124P]PVPRPVEPPGDLGLPTEPQDTPG GPA SOX17 c.1208G>T p.S403I PYQGHDSGVNLPDSHGAISSVVSDA[p. VSDAISAVY,ISAVYYCNY,VVSDAISAV,ISSVVSDAI,SDAISA UCEC S403I]ISAVYYCNYPDV* VYY,VVSDAISAVY,VSDAISAVYY,SVVSDAISAV,AISSVVSD AI,AISAVYYCNY SOX6 c.2155C>T p.R719W HLEKYPNYKYKPRPKRTCIVDGKKL[p.R LWIGEYKQL,GKKLWIGEY,KLWIGEYKQL,LWIGEYKQLM, CRC 719W]WIGEYKQLMRSRRQEMRQFFT WIGEYKQLMR VGQQP SOX7 c.925de|C p.L309fs RRIPHLPGHPYSPEYAPSPLHCSHP[p.L3 SHPWAPWPL,SPLHCSHPW,HPWAPWPLA,HCSHPWAP STAD 09fs]WAPWPLASPPASP* W,WPLASPPAS,CSHPWAPWPL,APWPLASPPA,LHCSHP WAPW,HPWAPWPLAS SOX9 c.223G>A p.E75K ENTFPKGEPDLKKESEEDKFPVCIR[p.E7 CIRKAVSQV,RKAVSQVLK,FPVCIRKAV,IRKAVSQVL,CIRKA LUAD 5K]KAVSQVLKGYDWTLVPMPVRVNG VSQVL,IRKAVSQVLK,KAVSQVLKGY,FPVCIRKAVS SSK SP4 c.17_19 p.E11de| MSDQKKEEEE[p.E11de|]AAAAAAMA KEEEEAAAA,KEEEEAAAAA LUSC de|AGG TEGGKTSEPENNNKKPKTSG SP4 c.19G>A p.E7K MSDQKK[p.E7K]KEEEEAAAAAAMATE KEEEEAAAA,KEEEEAAAAA TGCT GGKTSEPENNN SPAG16 c.1315G>T p.V439L GDTTVKLWDLCKGDCILTFEGHSRA[p. ALWSCTWHS,HSRALWSCT,FEGHSRALW,SRALWSCTW,R LUAD V439L]LWSCTWHSCGNFVASSSLDKTS ALWSCTWH,ALWSCTWHSC,LTFEGHSRAL,TFEGHSRALW, KIWD HSRALWSCTW SPAG16 c.1462C>T p.P488S WDVNSERCRCTLYGHTDSVNSIEFF[p.P EFFSFSNTL,NSIEFFSFS,VNSIEFFSF,IEFFSFSNT,FSFSNTLLT, SKCM 488S]SFSNTLLTSSADKTLSIWDARTGICE SVNSIEFFSF,EFFSFSNTLL,IEFFSFSNTL,FSFSNTLLTS SPAG17 c.3790 p.Q1264fs GQESTGQYVIDEEPTWDIMVRQSYP[p. IMVRQSYPR,MVRQSYPRG,DIMVRQSYPR STAD de|C Q1264fs]RG* SPAM1 c.1037G>A p.R346Q LVYTFGETVALGASGIVIWGTLSIM[p.R IMQSMKSCL,MQSMKSCLL,TLSIMQSMK,GTLSIMQSM,Q GBM 346Q]QSMKSCLLLDNYMETILNPYIINV SMKSCLLL,IMQSMKSCLL,SIMQSMKSCL,MQSMKSCLLL,G TL TLSIMQSMK,WGTLSIMQSM SPATA17 c.215G>A p.R72K QVRAYIRHLNRIVTIIQKWWRSFLG[p.R FLGKKQYQL,KWWRSFLGK,WWRSFLGKK,RSFLGKKQY,G CESC 72K]KKQYQLTVQVAYYTMMMNLYNA KKQYQLTV,FLGKKQYQLT,SFLGKKQYQL,KWWRSFLGKK, MAVR WRSFLGKKQY,KKQYQLTVQV SPATA22 c.449C>T p.S150L NDFKPQCKRTNLVANDGKNSCPVSS[p. VSSVAQQQK,SVAQQQKQLR,GKNSCPVSSV CRC S150L]VAQQQKQLRIPEPPNLSRNKET ELLR SPATA c.2055 p.C685fs KVCTKTMPIGPDVSLENLAAETCFF[p.C LAAETCFFL,LILETSAQK,KLLCWLCKK,ETCFFLELI,AETCFFL STAD 5L1 de|T 685fs]LELILETSAQKLLCWLCKKMD* EL,LETSAQKLL,LELILETSA,NLAAETCFFL,FLELILETSA,LILET SAQKL,KLLCWLCKKM,AQKLLCWLCK,ETCFFLELIL,AETCFF LELI SPATA9 c.566G>T p.C189F AVLKKVKNIFQEEESIRQNREESEN[p.C FRKAFSEPV,EESENFRKA,NFRKAFSEPV,RQNREESENF,EE KIRC 189F]FRKAFSEPVLSEPMFAEGEIKAKP SENFRKAF,FRKAFSEPVL,REESENFRKA YR SPEG c.2831C>T p.A944V EAEGGLCRLRILAAERGDAGFYTCK[p.A YTCKVVNEY,DAGFYTCKV,FYTCKVVNEY CRC 944V]VVNEYGARQCEARLEVRAHPESR SLA SPEG c.2975_29 p.A992fs AVLAPLQDVDVGAGEMALFECLVAG[p. FECLVAGAH,ALFECLVAGA KIRC 76insG A992fs]AH* SPEN c.2407_240 p.E803fs RLERYTKNEKTDKERTFDPERVERE[p.E TLNTEGKSGK GBM 8de|GA 803fs]TLNTEGKSGKGQN* SPESP1 c.363C>G p.F121L EETTTFPTGGFTPEIGKKKHTESTP[p.F1 KKHTESTPL,KHTESTPLW,TESTPLWSI,KKKHTESTPL,KKHT BLCA 21L]LWSIKPNNVSIVLHAEEPYIENEEPE ESTPLW SPG20 c.696de|T p.F232fs QPPPLETLGLDADELILIPNGVQIF[p.F2 IPNGVQIFL,LIPNGVQIFL STAD 32fs]L* SPIN2B c.448A>G p.M150V ANTIIGKAVEHMFEGEHGSKDEWRG[p. KDEWRGVVL,VVLAQAPIM,DEWRGVVLA,VVLAQAPIMK, TGCT M150V]VVLAQAPIMKAWFYITYEKDP SKDEWRGVVL,RGVVLAQAPI,DEWRGVVLAQ VLYMY SPIN4 c.512A>G p.Y171C PVMDTWFYITYEKDPVLYMYTLLDD[p. YMYTLLDDC,YMYTLLDDCK LUAD Y171C]CKDGDLRIIPDSNYYFPTAEQEP GEV SPINT1 c.947C>T p.A316V LREEECILACRGVQGGPLRGSSGAQ[p. VTFPQGPSM,GSSGAQVTF,RGSSGAQVTF,AQVTFPQG GBM A316V]VTFPQGPSMERRHPVCSGTCQ PS PTQFR SPOP c.148G>A p.E50K TQIKVVKFSYMWTINNFSFCREEMG[p. KVIKSSTFS,GKVIKSSTF,FSFCREEMGK,MGKVIKSSTF UCEC E50K]KVIKSSTFSSGANDKLKWCLRVN PKG SPOP c.304T>G p.F102V DEESKDYLSLYLLLVSCPKSEVRAK[p.F1 KSEVRAKVK,RAKVKFSIL,KVKFSILNA,SEVR PRAD 02V]VKFSILNAKGEETKAMESQRAYRF AKVKF,KVKFSILNAK,RAKVKFSILN,EVRAKVKFSI,KSE VQ VRAKVKF,VRAKVKFSIL,AKVKFSILNA,CPKSEVRAKV SPOP c.305T>G p.F102C DEESKDYLSLYLLLVSCPKSEVRAK[p.F1 KSEVRAKCK,RAKCKFSIL,KCKFSILNA,SEVRAKCKF, PRAD 02C]CKFSILNAKGEETKAMESQRAYRF RAKCKFSILN,KCKFSILNAK,EVRAKCKFSI,KSEVRAKCKF, VQ VRAKCKFSIL SPOP c.391T>G p.W131G ILNAKGEETKAMESQRAYRFVQGKD[p. QGKDGGFKK,GGFKKFIRR,GKDGGFKKF,RFVQGKDGGF PRAD W131G]GGFKKFIRRDFLLDEANGLLPD DKLT SPOP c.397T>A p.F133I NAKGEETKAMESQRAYRFVQGKDWG[p. FVQGKDWGI,DWGIKKFIR,WGIKKFIRR,GKDWGIKKF,RFV PRAD F133I]IKKFIRRDFLLDEANGLLPDDKL QGKDWGI,DWGIKKFIRR TLF SPOP c.397T>G p.F133V NAKGEETKAMESQRAYRFVQGKDWG[p. FVQGKDWGV,DWGVKKFIR,GKDWGVKKF,DWGVKKFIRR PRAD F133V]VKKFIRRDFLLDEANGLLPDD KLTLF SPOP c.398T>G p.F133C NAKGEETKAMESQRAYRFVQGKDWG[p. DWGCKKFIR,GKDWGCKKF,DWGCKKFIRR PRAD F133C]CKKFIRRDFLLDEANGLLPDDK LTLF SPOP c.399C>G p.F133L NAKGEETKAMESQRAYRFVQGKDWG[p. FVQGKDWGL,DWGLKKFIR,GKDWGLKKF,LKKFIRRDF,FV PRAD F133L]LKKFIRRDFLLDEANGLLPDDK QGKDWGLK,RFVQGKDWGL,DWGLKKFIRR LTLF SPTA1 c.5195A>C p.K1732T EKLKEAYALFQFFQDLDDEESWIEE[p.K WIEETLIRV,EESWIEETL,SWIEETLIRV,TLIRVSSQDY,ESWIE STAD 1732T]TLIRVSSQDYGRDLQGVQNLLK ETLIR,DEESWIEETL,EESWIEETLI KHKR SPTA1 c.6032C>T p.A2011V PEITDLKDKLISAQHNQSKAIEERY[p.A2 RYVALLKRW,AIEERYVAL,KAIEERYVA,IEERYVALL,AIEERY GBM 011V]VALLKRWEQLLEASAVHRQKLLE VALL,KAIEERYVAL KQL SPTA1 c.6727G>T p.D2243Y DLGDNLEDALILDIKYSTIGLAQQW[p.D LAQQWYQLY,GLAQQWYQL,QQWYQLYQL,WYQLYQLGL, LUAD 2243Y]YQLYQLGLRMQHNLEQQIQAK AQQWYQLYQ,STIGLAQQWY,AQQWYALYQL,QWYQLYQ DIKGV LGL,GLAQQWYQLY,WYQLYQLGLR,YQLYQLGLRM SPTA1 c.7099G>T p.G2367C FLIDKESENIKSSDEIENAFQALAE[p.G2 ALAECKSYI,QALAECKSY,ALAECKSYIT,NAFQALAECK,FQA LUAD 367C]CKSYITKEDMKQALTPEQVSFCA LAECKSY,CKSYITKEDM THM SPTB c.256C>T p.R86C KWVNSHLARVSCRITDLYKDLRDGR[p. RLLIKLLEV,LLIKLLEVL,RDGRLLIKL,RLLIKLLEVL,DLRDGRLL CRC R86C]LLIKLLEVLSGEMLPKPTKGKMRI IK HC SPTB c.5591C>T p.T1864I AFERELHLLGVQVQQFQDVATRLQT[p. ATRLQTVYA,VATRLQTVY,DVATRLQTV,RLQTVYAGEK,VY KIRC T1864I]VYAGEKAEAIQNKEQEVSAAW AGEKAEAI,ATRLQTVYAG,TVYAGEKAEA,DVATRLQTVY,L QALLD QTVYAGEKA SPTBN4 c.5978C>T p.A1993V ADKPRDVSSVEVLMNYHQGLKTELE[p. ELEVRVPEL,TELEVRVPE,GLKTELEVRV,HQGLKTELEV,TEL CRC A1993V]VRVPELTTCQELGRSLLLNKSA EVRVPEL,LEVRVPELTT MADE SPTLC3 c.290G>A p.R97K IGTLFGYLRDFLRNWGIEKCNAAVE[p.R KKEQKDFVPL SKCM 97K]KKEQKDFVPLYQDFENFYTRNLYM RI SPTY2D1 c.1454de|C p.P485fs GSSRGPGRPVSSPHELRRPVSGLGP[p.P GPRGGLSVA,GLGPRGGLSV,GPRGGLSVAL STAD 485fs]RGGLSVALGDP* SRCAP c.5625_562 p.Q1875fs RSGPPSPPSTATSFGGPRPRRQPPP[p. GLPGGKAEA,RQPPPTTSF,TSFPFLSGL,RPRRQPPPT,FPFLS KIRP 6insC Q1875fs]TTSFPFLSGLPGGKAEAAAV* GLPG,FLSGLPGGKA,GLPGGKAEAA,TTSFPFLSGL,RPRRQP PPTT,QPPPTTSFPF,RRQPPPTTSF,FPFLSGLPGG SRCAP c.5626_562 p.P1876fs RSGPPSPPSTATSFGGPRPRRQPPP[p.P GLPGGKAEA,RQPPPTTSF,TSFPFLSGL,RPRRQPPPT,FPFLS STAD 7insC 1876fs]TTSFPFLSGLPGGKAEA GLPG,FLSGLPGGKA,GLPGGKAEAA,TTSFPFLSGL,RPRRQP AAV* PPTT,QPPPTTSFPF,RRQPPPTTSF,FPFLSGLPGG SRCIN1 c.2595de|C p.P865fs LSQSPKKVTAETDFNKSVDFEMPPP[p. FEMPPPAPR,VDFEMPPPA,DFEMPPPAPR STAD P865fs]APR* SREBF2 c.2289de|C p.H763fs LSRAQSLCGPEHSAVPDSLRWLCHP[p. RWLCHPWAR,RSFSWSGAG,HPWARSFSW,SLRWLCHPW,LCH STAD H763fs]WARSFSWSGAGL* PWARSF,SLRWLCHPWA,CHPWARSFSW,RW LCHPWARS,WARSFSWSGA,RSFSWSGAGL,HPWARSFSWS, WLCHPWARSF,DSLRWLCHPW SRGAP1 c.182C>T p.T61M EQQTEMRVQLLQDLQDFFRKKAEIE[p. MEYSRNLEK,KKAEIEMEY,IEMEYSRNL,RKKAEIEMEY,MEY MM T61M]MEYSRNLEKLAERFMAKTRSTK SRNLEKL DHQQ SRPRB c.40G>A p.G14S MASADSRRVADGG[p.G14S]SAGGTF SAGGTFQPY,GSAGGTFQPY,ADGGSAGGTF BLCA QPYLDTLRQELQQTDPTLLS SRRM2 c.6769G>T p.A2257S IPAASAAAMNLASARTPAIPTAVNL[p. NLSDSRTPA,NLSDSRTPAA TGCT A2257S]SDSRTPAAAAAMNLASPRTAV APSAV SRSF11 c.51_52ins p.G17fs MSNTTVVPSTAGPGPSGG[p.G17fs]A RWRRWWWRR,RWWWRRRRR,GARWRRWWWR,RWR PRAD G RWRRWWWRRRRRHRGNPGD* RWWWRRR,RWWWRRRRRH,WWWRRRRRHR SSPO c.12593de| p.S4198fs PRGQQSRFRSSTSGSWAPECREEQS[p. ALAPAPWGT,ALSPRAHPC,RASPALSPR,SASGAPAPR,QSR PRAD C S4198fs]RASPALSPRAHPCACRALAPA ASPALS,RAHPCACRA,RGSASGAPA,SPALSPRAH,SPRAHP PWGTAGCRGSASGAPAPRRV* CAC,APAPWGTAG,EQSRASPAL,CRALAPAPW,EEQSRASP A,ALAPAPWGTA,ALSPRAHPCA,GSASGAPAPR, RASPALSPRA,RAHPCACRAL,REEQSRASPA,EEQSRAS PAL,ACRALAPAPW ST18 c.2334C>A p.H778Q KTLKSLMAANSQELKCPTPGCDGSG[p. GSGQVTGNY,GQVTGNYAS,QVTGNYASHR,GQVTGNYAS LUAD H778Q]QVTGNYASHRSLSGCPRARKG H GVKMT ST6GA c.1061G>A p.S354N ELNYSLVQKVVTRFPPVPQQQLLLA[p.S LLANLPAGS,QQQLLLANL,LANLPAGSL,LLANLPAGSL, TGCT LNAC1 354N]NLPAGSLRCITCAVVGNGGILNN NLPAGSLRCI,LANLPAGSLR,QQLLLANLPA SHM STAB1 c.3358_335 p.P1120fs ASVDVADLLATNGVLHILSQVLLPP[p.P GLGACLQPL,RGCARWAGV,CARWAGVAA,RWAGVAAAA, STAD 9insC 1120fs]PRGCARWAGVAAAAGLGACL IAAAPWVGA,QPLPGIAAA,ARWAGVAAA,LQPLPGIAA, QPLPGIAAAPWVGAPD* LPGIAAAPW,GIAAAPWVGA,RGCARWAGVA,CAR WAGVAAA,LLPPPRGCAR,ARWAGVAAAA,AAAAGLGACL, AGLGACLQPL,LQPLPGIAAA,LPPPRGCARW, LPGIAAAPWV STAC3 c.349G>T p.G117W FKDHFFKKPKFCDVCARMIVLNNKF[p. VLNNKFWLR,WLRCKNCKT,IVLNNKFWLR,RMIVLNNKFW, LUAD G117W]WLRCKNCKTNIHEHCQSYVE KFWLRCKNCK,MIVLNNKFWL MQRCFG STAM c.427T>C p.Y143H TDELKNDLLKKYNVEYQEYLQSKNK[p.Y KHKAEILKK,YLQSKNKHKA,KNKHKAEILK,SKNKHKAEIL TGCT BPL1 143H]HKAEILKKLEHQRLIEAERKRIAQ MR STARD8 c.1985G>C p.G662A RRNKTPDYRGQHVFGVPPLIHVQRT[p. HVQRTAQPL,RTAQPLPQSI,IHVQRTAQPL TGCT G662A]AQPLPQSIQQAMRYLRSQCLD QVGIF STAT2 c.1466_146 p.P489fs AWASVLWFNLLSPNLQNQQFFSNPP[p. LLCWPRPQL,AVLLLCWPR,FSNPPNGPL,ELAGPCSQL,NPP STAD 7insC P489fs]NGPLELAGPCSQLAVLLLCWP NGPLEL,WPRPQLRPA,RPQLRPAEH,QQFFSNPPN,AEHAE RPQLRPAEHAEKQAVRAEL* KQAV,LLLCWPRPQL,QLRPAEHAEK,SQLAVLLLCW,LAVLL LCWPR,LLCWPRPQLR,ELAGPCSQLA,WPRPQLRPAE,RPQ LRPAEHA,RPAEHAEKQA,QQFFSNPPNG,FFSNPPNGPL,LE LAGPCSQL,AEKQAVRAEL STAT3 c.1982A>T p.D661V SVEPYTKQQLNNMSFAEIIMGYKIM[p. IIMGYKIMV,IMGYKIMVA,IMVATNILV,KIMVATNIL,YKIM HNSC D661V]VATNILVSPLVYLYPDIPKEEAFG VATNI,IIMGYKIMVA,KIMVATNILV,IMGYKIMVAT,GYKIM KY VATNI,EIIMGYKIMV,YKIMVATNIL,IMVATNILVS, VATNILVSPL STAT5B c.1101_110 p.P367fs KTQTKFAATVRLLVGGKLNVHMNPP[p. HMNPPPGEGH STAD 2insC P367fs]PGEGHHHQ* STAT6 c.1061_106 p.P354fs QVLKTQTKFQAGVRFLLGLRFLGAP[p.P LLCPVQEPA,ASGSWGWSR,SGSWGWSRK,SWGWSRKH KIRC 2insC 354fs]SQASAGQGRHGDREAGAGAEC W,RFLGAPSQA,WSRKHWRNH,WGWSRKHWR,REAGAG ASGSWGWSRKHWRNHQQHCALGEQ AEC,RNHQQHCAL,CALGEQHSW,GEQHSWELL,EQHSWE HSWELLLCPVQEPASQEDQAV* LLL,WELLLCPVQ,FLGAPSQASA,ALGEQHSWEL,HSWELLLCPV, LLLCPVQEPA,CASGSWGWSR,ASGSWGWSRK,HWR NHQQHCA,SWGWSRKHWR,LRFLGAPSQA,SQASAGQGRL H,REAGAGAECA,AGAECASGSW,AECASGSWGW,GSWG WSRKHW,RKHWRNHQQH,WRNHQQHCAL,QQHCALGE QH,GEQHSWELL STAT6 c.1402G>C p.D468H LGPGKLPIQLQALSLPLVVIVHGNQ[p.D HGNQHNNAK,NQHNNAKAT,NQHNNAKATI DLBCL 468H]HNNAKATILWDNAFSEMDRVPF VVAE STK11 c.837de|C p.G279fs EGDNIYKLFENIGKGSYAIPGDCGP[p.G YAIPGDCGPR,IPGDCGPRSL LUSC 279fs]RSLTC* STK11IP c.464C>A p.A155E PLHCLHGLRGIYSQLETLICSRSLQ[p.A1 SLQELEELL,QELEELLSA,LICSRSLQEL,RSLQELEELL,LQELEE KIRC 55E]ELEELLSACGGDFCSALPWLALLSA LLSA,QELEELLSAC N STK19 c.265G>A p.D89N RGARPGGGDAGGTPGETVRHCSAPE[p. SAPENPIFR,NPIFRFSSL,CSAPENPIF,CSAPENPIFR,SAPEN SKCM D89N]NPIFRFSSLHSYPFPGTIKSRDMS PIFRF,RHCSAPENPI,HCSAPENPIF,NPIFRFSSLH WK STK19 c.52_53ins p.R18fs MQKWFSAFDDAIIQRQWR[p.R18fs]G IIQRQWRGK,LPGRGRCEL,QRQWRGKPL,RQWRGKPLP,AI PRAD G KPLPGRGRCELHEGG* IQRQWRGK,QWRGKPLPGR,RGKPLPGRGR,IQRQWRGKP L,RQWRGKPLPG STOML3 c.256G>T p.D86Y VVFRLGRIQADKAKGPGLILVLPCI[p.D8 ILVLPCIYV,VLPCIYVFV,YVFVKVDLR,LVLPCIYVF,IYVFVKV LUAD 6Y]YVFVKVDLRTVTCNIPPQEILTRDSV DL,LILVLPCIY,LILVLPCIYV,LVLPCIYVFV,VLPCIYVFVK,ILVL PCIYVF,GLILVLPCIY,IYVFVKVDLR,LPCIYVFVKV STON1- c.1352A>G p.N451S KVTKEGKFVESAVITQIYCLCFVNG[p.N CLCFVNGSL,FVNGSLECF,GSLECFLTL,FVNGSLECFL,CFVN TGCT GTF2A 451S]SLECFLTLNDLELPKRDESYYEKDS GSLECF 1L E STRA6 c.203A>G p.Q68R QPAGNQTSPGATEDYSYGSWYIDEP[p. GSWYIDEPR BRCA Q68R]RGGEELQPEGEVPSCHTSIPPGL YHA STRADA c.997de|C p.R333fs EELTMSPSRSVANSGLSDSLTTSTP[p.R TLWSSAFSA,WSSAFSATR,VTRPPTPTT,ATRMPGPVP,TTL STAD 333fs]GPPTVTRPPTPTTEPSPPTSTTL WSSAFS,STTLWSSAF,SSAFSATRM,TRMPGPVPA,MPGPV WSSAFSATRMPGPVPAPS* PAPS,SPPTSTTLW,TLWSSAFSAT,FSATRMPGPV,TTLWSS AFSA,ATRMPGPVPA,STPGPPTVTR,LWSSAFSATR,TTSTP GPPTV,EPSPPTSTTL,TSTTLWSSAF,WSSAFSATRM STRN3 c.654G>T p.K218N LDVRSQRVRSLLGLSNSEPNGSVET[p.K ETNNLEQIL,VETNNLEQI,VETNNLEQIL UCEC 218N]NNLEQILNGGESPKQKGQEIKRS SGD STT3B c.1747G>T p.D583Y TSNAYSSPSVVLASYNHDGTRNILD[p.D ILDYFREAY,NILDYFREA,DYFREAYFW,YFREAYF CRC 583Y]YFREAYFWLRQNTDEHARVMS WL,GTRNILDYF,LDYFREAYF,GTRNILDYFR, WWDYG DYFREAYFWL,YFREAYFWLR,NILDYFREAY, ILDYFREAYF STX2 c.320G>T p.R107L KKTANKIRAKLKAIEQSFDQDESGN[p.R DESGNLTSV,LTSVDLRIRR LUAD 107L]LTSVDLRIRRTQHSVLSRKFVEAM AE STX2 c.756de|A p.K252fs MINNIERNVMNATDYVEHAKEETKK[p. NIRARQEGK,ETKKLSNIR STAD K252fs]LSNIRARQEGKSG* STXBP6 c.274G>A p.D92N QFEGSTSFVRRSQWMLEQLRQVNGI[p. RQVNGINPN,NPNGDSAEF,RQVNGINPNG UCEC D92N]NPNGDSAEFDLLFENAFDQWV ASTAS SULT1C4 c.254G>A p.R85Q WTQEIVELIQNEGDVEKSKRAPTHQ[p. QQFPFLEMK,QFPFLEMKI,APTHQQFPF,HQQFPFLEM,KR CRC R85Q]QFPFLEMKIPSLGSGLEQAHAM APTHQQF,HQQFPFLEMK,RAPTHQQF PSPR PF,KSKRAPTHQQ,APTHQQFPFL,SKRAPTHQQF,THQQFPFL EM,QQFPFLEMKI SULT1E1 c.230G>A p.R77Q WVSEIVYMIYKEGDVEKCKEDVIFN[p.R VIFNQIPFL,DVIFNQIPF,KEDVIFNQI,DVIFNQIPFL UCEC 77Q]QIPFLECRKENLMNGVKQLDEMN SPR SUMF2 c.329G>A p.G110E IFPVTNKDFRDFVREKKYRTEAEMF[p.G EMFEWSFVF,EWSFVFEDF,AEMFEWSFV,FEWSFVFED,EA LUAD 110E]EWSFVFEDFVSDELRNKATQPM EMFEWSF,TEAEMFEWS,AEMFEWSFVF,EAEMFEWSFV,T KSVL EAEMFEWSF,FEWSFVFEDF SUN3 c.1016C>A p.P339Q TFELQHAVSEYLLCVKLNIFSNWGH[p.P FSNWGHQKY,IFSNWGHQK,HQKYTCLYR,GHQKYTCLY,W LUAD 339Q]QKYTCLYRFRVHGTPGKHI* GHQKYTCLQKYTCLYRF,NIFSNWGHQ,HQKYTCLYRF,IFSNWG HQKY,WGHQKYTCLY SUN3 c.370C>A p.L124I LRMPKEQLELLKKESQNLENNFRQI[p.L QIIFLIEQI,NFRQIIFLI,LENNFRQI,RQIIFLIEQ,RQIIFLIEQI, UCEC 124I]IFLIEQIDVLKALLRDMKDGMDNN IFLIEQIDVL,LENNFRQIIF HN SUN3 c.382G>A p.E128K KEQLELLKKESQNLENNFRQILFLI[p.E1 FLIKQIDVL,KQIDVLKAL,LIKQIDVLK,ILFLIKQIDV,KQIDVLK CRC 28K]KQIDVLKALLRDMKDGMDNNHN ALL,RQILFLIKQI,FLIKQIDVLK,NFRQILFLIK,IKQI WNTH DVLKAL SUPT6H c.2869G>A p.A957T SSDEDILCLKFHPLQEHVVKEELLN[p.A9 TLYCEFINR,LLNTLYCEF,VKEELLNTL,KEELLNTLY,LLNTLYC CRC 57T]TLYCEFINRVNEVGVDVNRAIAHP EFI,TLYCEFINRV,NTLYCEFINR,ELLNTLYCEF,VKEELLNTLY YS SUSD1 c.1027C>T p.R343C SRRINPKISYVISIKGQRLDPMESV[p.R3 MESVCEETV,CEETVNLTT UCEC 43C]CEETVNLTTDSRTPEVCLALYPGTN Y SUSD5 c.1538C>T p.T513M YELTSSTLEILTVNTVKQTPNHIPS[p.T51 TPNHIPSMI,SMIMATTQP,MIMATTQPP,IPSMIMATT,MI GBM 3M]MIMATTQPPVETTVPEIQDSFPYLL MATTQPPV,KQTPNHIPSM,QTPNHIPSMI,TPNHIPSMIM, S SMIMATTQPP SV2A c.412de|G p.E138fs MADGAPLAGVRGGLSDGEGPPGGRG[p. 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KGICWKWPV,PWKGICWKW,CTRGGGKRK,RGGGKRKKK, STAD G1862fs]WWCTRGGGKRKKKMCKVS CWKWPVTVA,FQGGWWCTR,LQCFQGGWW,CKVSGGCT GGCTACVERCPWKGICWKWPVTVAA* A,WKWPVTVAA,VERCPWKGI,KVSGGCTACV,GICWKWP VTV,TACVERCPWK,CFLQCFQGGW,GWWCTRGGGK,CTR GGGKRKK,GGKRKKKMCK,CWKWPVTVAA,CFQGGWWC TR,CPWKGICWKW SYCP2 c.1422A>T p.K474N KPSKYIKNSDKGNRNNSQLEKTTPS[p.K KTTPSNRKM,NRKMSEASM,TPSNRKMSEA, HNSC 474N]NRKMSEASMIVSGADRYTMRSP SQLEKTTPSN,SNRKMSEASM VLFS SYMPK c.1007C>G p.A336G HPASLEFQAQITTLLVDLGTPQAEI[p.A3 IGRNMPSSK,PQAEIGRNM,AEIGRNMPS,TPQAEIGRNM, TGCT 36G]GRNMPSSKDTRKRPRDDSDSTLK AEIGRNMPSS KMK SYN2 c.99_101de| p.A34de| LSDSSFIANLPNGYMTDLQRPEPQQ[p. LQRPEPQQPT BLCA,KIRP, AGC A34de|]PTPPPPGPGAASAAAPPTASP PRAD GPERTPP SYNDIG1 c.403G>T p.D135Y CCETTFIEDRSPTKDSLEYPDGKFI[p.D1 YLSADDIKI,FIYLSADDI,YPDGKFIYL,FIYLSADDIK,EYPDG LUAD 35Y]YLSADDIKIHTLSYDVEEEEEFQELE KFIYL,KFIYLSADDI,IYLSADDIKI,LEYPDGKFIY SYNE2 c.9309G>T p.K3103N ESRRLNAQILSQRIEKAKCLCDEII[p.K31 CLCDEIINK,IINKLNENK,NKLNENKTF,CLCDEIINKL CRC 03N]NKLNENKTFDDSFKEKEILQIKLNA E SYNGR4 c.506G>A p.R169Q QAAIAFTFFSILVWIFOAYLAFQDL[p.R1 LQNDAPVPY,FQDLQNDAPV,LQNDAPVPYK,DLQN CRC 69Q]QNDAPVPYKRFLDEGGMVLTTLP DAPVPY LPS SYNJ1 c.2041A>T p.I681F KTISRDNKYVLLASEQLVGVCLFVF[p.I6 FVFFRPQHA,GVCLFVFFR,VGVCLFVFF,FFRPQHAPF,VFFR CLL 81F]FRPQHAPFIRDVAVDTVKTGMGG PQHAPF,FFRPQHAPFI,VGVCLFVFFR ATG SYNJ2 c.2495A>C p.K832T WRKKHPFDKTAGELNLLDSDLDVDT[p. TVRHTWSPG,TVRHTWSPGA KIRC K832T]TVRHTWSPGALQYYGRAELQA SDHRP SYNJ2 c.3331_333 p.P1111fs HRSPSRSLSVPNRPRPPQPPQRPPP[p.P1 HLLRHPWTV,TVFNFADGK,TSQGSDWNK,RFNGEKVGF,RH STAD 2insC 111fs]SNRFNGEKVGFRCVHLLRHPW PWTVFNF,KVGFRCVHL,GFRCVHLLR,KTSTRSTSA,STRST TVFNFADGKTSTRSTSATSQGSDWNK* SATS,LLRHPWTVF,CVHLLRHPW,HPWTVFNFA,GEKVGFR CV,VGFRCVHLLR,WTVFNFADGK,ATSQGSDWNK,HLLRH PWTVF,LRHPWTVFNF,KVGFRCVHLL,GFRCVHLLRH, KTSTRSTSAT,STRSTSATSQ,RFNGEKVGFR,NFADGKT STR,PQRPPPSNRF,NRFNGEKVGF,RCVHLLRHPW SYNM c.1547G>A p.R516Q RTVILGKKTEVKATREQERNRPETI[p.R5 TIQTKPEEK,IQTKPEEKM,RNRPETIQTK,IQTKPEEKMF UCEC 16Q]QTKPEEKMFDSKEKASEERNLRW EEL SYNPO c.1856_185 p.G619fs SSHLKGQAVPASKTGILEESMARRG[p. GQPQIHVYF,MARRGQPQI,RGQPQIHVY,QPQIHVYFR,AQ KIRC 7insC G619fs]QPQIHVYFRGEAQGDPESRLA GDPESRL,SMARRGQPQI,RGQPQIHVYF,MARRGQPQIH,R GSGTDSG* RGQPQIHVY SYT4 c.1de|A p.M1fs [p.M1fs]WLRSPPAGKNLMKSPQWW HLAWSSQSL,SLSLHGSAV,CLRELIFTL,LLHTSLCMC,SLCMC STAD GSSVHLAWSSQSLSLHGSAVRENHPSL LREL,WLRSPPAGK,HTSLCMCLR,QWWGSSVHL,AVRENH TRLLHTSLCMCLRELIFTLKT* PSL,LTRLLHTSL,LSLHGSAVR,SPPAGKNLM,SPQWWGSSV, RLLHTSLCM,KNLMKSPQW,PQWWGSSVH,WGSSVHLA W,AWSSQSLSL,CMCLRELIF,RELIFTLKT,SLTRLLHTSL,LLHT SLCMCL,SLCMCLRELI,CLRELIFTLK,WWGSSVHLAW,KSPQ WWGSSV,AVRENHPSLT,SLSLHGSAVR,HPSLTRLLHT,LA WSSQSLSL,GKNLMKSPQW,PQWWGSSVHL,VHLAWSSQ SL,SQSLSLHGSA,SAVRENHPSL,RENHPSLTRL,TRLLHTSLC M,LCMCLRELIF,SPQWWGSSVH SYT7 c.1046C>T p.T349M TMKRNLNPIFNESFAFDIPTEKLRE[p.T3 KLREMTIII,IPTEKLREM,REMTIIITV,EMTIIITVM,MTIIITV CRC 49M]MTIIITVMDKDKLSRNDVIGKIYLS MDK,KLREMTIIIT,REMTIIITVM W SYT8 c.1117C>T p.R373W GARASGQPLQHWADMLAHARRPIAQ[p. QWHPLRPAR,PIAQWHPLR,RPIAQWHPL,HARRPIAQW,A ACC R373W]WHPLRPAREVDRMLALQPR QWHPLRPA,HARRPIAQWH,RPIAQWHPLR,AHARRPIAQ LRLRLPL W,RRPIAQWHPL SYTL2 c.1320C>G p.I440M FPINGLHSHSEVLTARPQSMENSPT[p. QSMENSPTM,PQSMENSPTM BLCA I440M]MNEPKDKSSELTRLESVLPRSPA DEL TAB3 c.632G>C p.R211T HIPRYSTNPITVTVSQNLPSGQTVP[p.R QTVPTALQI,LPSGQTVPT,TALQILPQI,GQTVPTALQI,LPSG BLCA 211T]TALQILPQIPSNLYGSPGSIYIRQT QTVPTA S TADA2B c.199G>A p.E67K IGHHRRYHGYQLVDGGRFTLWGPEA[p. FTLWGPEAK,EAKGGWTSR,RFTLWGPEAK CESC E67K]KGGWTSREEQLLLDAIEQFGFG NWED TAF1 c.2527C>T p.R843W SKDRPRRIRMEDIKKAFPSHSESSI[p.R8 IWKRLKLCA,HSESSIWKR,SESSIWKRL,FPSHSESSIW,WKR UCEC 43W]WKRLKLCADFKRTGMDSNWWV LKLCADF LKSDF TAF1A c.514_515C p.R172M HGMLKDAKRNLSEAETWRHGENTSS[p. SSMEILINL,SMEILINLI,NTSSMEILI,RHGENTSSM,GENTSS SKCM G>AT R172M]MEILINLIQAYKGLLQYYTWSE MEI,MEILINLIQ,SSMEILINLI,WRHGENTSSM,GENTSSMEI KKMEL L,MEILINLIQA TAF1B c.874C>T p.R292C GIESWPDYEDIYKKTVEVGTFLDLP[p.R GTFLDLPCF,LDLPCFPDI,FLDLPCFPDI,VGTFLDLPCF BLCA 292C]CFPDITEDCYLHPNILCMKYLMEV NL TAF1L c.2553de|A p.K851fs QVFIYRLFWKSKDRPRRIRMEDIKK[p.K DIKKPFLPI,RMEDIKKPF,MEDIKKPFL,KPFLPIQKAA,IRMED STAD 851fs]PFLPIQKAASGRG* IKKPF,RMEDIKKPFL TAF5 c.388T>G p.S130A RQSKLREAEEALRREAGLLEEAVAG[p.S LLEEAVAGA,EEAVAGAGA,GLLEEAVAGA,LEEAVAGAGA ACC 130A]AGAPGEVDSAGAEVTSALLSRVT ASA TANK c.1139C>T p.S380L LDSPGKAIRGPQQPIWKPFPNQDSD[p. NQDSDLVVL,FPNQDSDLV,KPFPNQDSDL,FPNQDSDLVV CRC S380L]LVVLSGTDSELHIPRVCEFCQAV FPP TAOK2 c.2696_269 p.Q899fs QRVEEELLALQTGRSERIRSLLERQ[p.Q RIRSLLERQG KIRC 7insG 899fs]GP* TARBP1 c.2344C>G p.L782V VLTELINLHLKVGWKRGNPIWRVIS[p.L RVISVLKNA,IWRVISVLK,NPIWRVISV,VLKNASIQHL,PIWR LUSC 782V]VLKNASIQHLQEMDSGQEPTVG VISVLK,NPIWRVISVL SAIQ TARS2 c.595G>A p.E199K RGSELPVLERICQELTAAARPFRRL[p.E1 AARPFRRLK,RLKASRDQL,RPFRRLKAS,AAARPFRRLK,AAR LUAD 99K]KASRDQLRQLFKDNPFKLHLIEEKV PFRRLKA,RPFRRLKASR,RLKASRDQLR,RRLKASRDQL T TARSL2 c.1097G>A p.G366D KGPHVRHTGKIKTIKIFKNSSTYWE[p.G TYWEDNPEM,STYWEDNPEM,WEDNPEMETL GBM 366D]DNPEMETLQRIYGISFPDNKMM RDWE TAS1R2 c.808C>T p.R270C PNQNMTSEERQRLVTIVDKLQQSTA[p. KLQQSTACV,LQQSTACVV,STACVVVVF,QSTACVVVV, CRC R270C]CVVVVFSPDLTLYHFFNEVLRQ QQSTACVVV,KLQQSTACVV,QQSTACVVVV,STACVVVV NFTG FS,LQQSTACVVV,QSTACVVVVF TAS1R3 c.1573G>A p.E525K SRQCQEGQVRRVKGFHSCCYDCVDC[p. CVDCKAGSY,CVDCKAGSYR BLCA E525K]KAGSYRQNPDDIACTFCGQDE WSPER TAS2R1 c.549C>A p.F183L KFFSQNATIQKEDTLAIQIFSFVAE[p. QIFSFVAEL,FVAELSVPL,FSFVAELSV,ELSVPLLIF,AELSVPLLI, CRC F183L]LSVPLLIFLFAVLLLIFSLGR IQIFSFVAEL,FVAELSVPLL,IFSFVAELSV,SF HTRQM VAELSVPL,LSVPLLIFLF,ELSVPLLIFL,FSFVAELSVP, AELSVPLLIF TAS2R16 c.531G>T p.Q177H IQLLTMEHLPRNSTVTDKLENFHQY[p. QYHFQAHTV,HFQAHTVAL,LENFHQYHF,FHQYHFQAH,H LUAD Q177H]HFQAHTVALVIPFILFLASTIFL QYHFQAHT,YHFQAFITVA,HQYHFQAHTV,KLENFHQYHF, MAS YHFQAHTVAL TAS2R16 c.691G>A p.V231I QIQHHSTGHCNPSMKARFTALRSLA[p. RSLAILFIV,FTALRSLAI,ILFIVFTSY,SLAILFIVF,ALRSLAILF,T MM V231I]ILFIVFTSYFLTILITIIGTLF ALRSLAIL,ALRSLAILFI,FTALRSLAIL,SLAILFIVFT,RFTALRSL DKRC AI,TALRSLAILF,RSLAILFIVF,ILFIVFTSYF,AILFIVFTSY TAS2R30 c.707_708 p.L236fs HGKGSQDPSTKVHIKALQTVTSFLL[p.L FLLVMCHLL,LVMCHLLSV,HLLSVHDHI,SFLLVMCHL,QTVT KICH insT 236fs]VMCHLLSVHDHISL* SFLLV,TVTSFLLVM,VMCHLLSVH,LSVHDHISL,LLVMCHLL SV,LLSVHDHISL,SFLLVMCHLL,QTVTSFLLVM,LVMCHLLS VH,LQTVTSFLLV,TSFLLVMCHL TAS2R38 c.932T>C p.I311T MAACPSGHAAILISGNAKLRRAVMT[p. AVMTTLLWA,TLLWAQSSL,RAVMTTLLW,KLRRAVMTT,L KIRC I311T]TLLWAQSSLKVRADHKADSRTL RRAVMTTL,RRAVMTTLL,KLRRAVMTTL,TLLWAQSSLK,RR C* AVMTTLLW,RAVMTTLLWA,TTLLWAQSSL,LRRAVMTTLL TAS2R41 c.763G>A p.A255T TRALKSLISFLILYALSFLSLIIDA[p.A FLSLIIDAT,LIIDATKFI,LSLIIDATK,SLIIDATKF,IDATKFISM,S GBM 255T]TKFISMQNDFYWPWQIAVYLCISVHP LIIDATKFI,LSLIIDATKF,IIDATKFISM,TKFISMQNDF TAS2R8 c.294G>C p.W98C PDVYTKNKQQIVIFTFWTFANYLNM[p. YLNMCITTC,FANYLNMCI,LNMCITTCL,CITTCLNVF,YLN TGCT W98C]CITTCLNVFYFLKIASSSHPLFLW MCITTCL,NMCITTCLNV,TFANYLNMCI,CITTCLNVFY, LK MCITTCLNVF TAS2R9 c.487G>C p.E163Q FLISLIISVPKNDDMWYHLFKVSHE[p.E1 HEQNITWKF,FKVSHEQNI,VSHEQNITW,VSHEQNITWK,K BLCA 63Q]QNITWKFKVSKIPGTFKQLTLNLG VSHEQNITW,SHEQNITWKF VM TAT c.1100G>A p.R367H TLSFLKSNADLCYGALAAIPGLRPV[p.R3 GLRPVHPSG,PVHPSGAMY,RPVHPSGAM,HPSGAMYLM, GBM 67H]HPSGAMYLMVGIEMEHFPEFEND GLRPVHPSGA,RPVHPSGAMY,HPSGAMYLMV,AAIPGLRP VEF VH,LRPVHPSGAM TBC1D1 c.212C>T p.S71F EVRRLSRQSTRKEPVTKQVRLCVSP[p.S RLCVSPFGL,QVRLCVSPF,RLCVSPFGLR,KQVRLCVSPF,QV BLCA 71F]FGLRCEPEPGRSQQWDPLIYSSIFEC RLCVSPFG,VRLCVSPFGL TBC1D1 c.830A>G p.H277R DGGLRSSGFFSSFEESDIENHLISG[p.H2 HLISGRNIV,DIENHLISGR KIRC 77R]RNIVQPTDIEENRTMLFTIGQSEVYL TBC1D12 c.1823T>A p.F608Y PDVGYVQGMSFIAAVLILNLEEADA[p.F NLEEADAYI,AYIAFANLL,EADAYIAFA,DAYIAFANL,EEADA KIRC 608Y]YIAFANLLNKPCQLAFFRVDHSM YIAF,LNLEEADAY,LEEADAYIA,YIAFANLLNK,ILNLEEADAY, MLK DAYIAFANLL,LEEADAYIAF,EEADAYIAFA,ADAYIAFANL TBC1D2B c.2759G>A p.R920Q ILDARKLISISFGDLNPFPLRQIRN[p.R92 QIRNQRAYH,NQRAYHLEK,RQIRNQRAY,IRNQRAYHL,RQI BLCA,KIRP, 0Q]QRAYHLEKVRLELTELEAIREDFLRE RNQRAYH,QIRNQRAYHL,RNQRAYHLEK,LRQIRNQRAY, PRAD NQRAYHLEKV TBC1 c.3697C>A p.P123 DWAITFEQFLASLLTEPALVKYFDK[p.P ALVKYFDKT,KTVCMMARI,KYFDKTVCM,YFDKTVCMM,AL PRAD D9 3T 1233T]TVCMMARITSAKNIRMMGKPL VKYFDKTV,KYFDKTVCMM,VKYFDKTVCM TSASD TBCD c.1426C>T p.R476C DEKRGACSVGTNVRDAACYVCWAFA[p. YVCWAFACA,CAYEPQELK,VCWAFACAY,YVCWAFACAY,F LUSC R476C]CAYEPQELKPFVTAISSALVIA ACAYEPQEL AVFD TBL1X c.377de|A p.N126fs DKLAQQQAAAAAAAAAAASQQGSAK[p. QMGRRMEHI,KTQQMGRRM,MGRRMEHIL,ASQQGSAK STAD R1 N126fs]MEKTQQMGRRMEHIL* M,AKMEKTQQM,QQMGRRMEH,QQMGRRMEHI,SQQG SAKMEK,AASQQGSAKM,QQMGRRMEH TBX3 c.559C>T p.H187Y RYKFHNSRWMVAGKADPEMPKRMYI[p. YIYPDSPAT,EMPKRMYIY,MYIYPDSPA,RMYIYPDSP,RMYI BRCA H187Y]YPDSPATGEQWMSKVVTFH YPDSPA,PEMPKRMYIY KLKLTNN TBX4 c.1109de|C p.S370fs LDLPCKRSYLEAPSSVGEDHYFRSP[p.S3 RSPLPTTSK,GEDHYFRSPL STAD 70fs]LPTTSKC* TCEB3 c.922G>A p.E308K DLLSAFEAMTSQANPEALSAPALQE[p. LSAPALQEK,KAAFPGRRV,LQEKAAFPG,ALSAPALQEK,AP SKCM C E308K]KAAFPGRRVNAKMPVYSGSRP ALQEKAAF ACQLQ TCF7 c.419A>C p.H140P GMYKETVYSAFNLLMHYPPPSGAGQ[p. QPPQPQPPL,GQPPQPQPPL KIRC H140P]PPQPQPPLHKANQPPHGVPQ LSLYEH TCHP c.515de|A p.E172fs KLREMELDLHQKHVVNSWEMQKEEK[p. MQKEEKNSK,NSKKPPQSK,QSKRTNGMK,RTNGMKMNM, STAD E172fs]NSKKPPQSKRTNGMKMNM KMNMKGPEG,MNMKGPEGR,NMKGPEGRR,SKRTNGM KGPEGRR* KM,RTNGMKMNMK,MQKEEKNSKK,KNSKKPPQSK,KMN MKGPEGR,NSKKPPQSKR,MNMKGPEGRR,KRTNGMKMN M,MKMNMKGPEG TCOF1 c.4084_4086 p.K1366de| GWESRKRKLSGDQPAARTPRSKKKK[p. RSKKKKLGA,TPRSKKKKL,RSKKKKLGAG PRAD de|AAG K1366de|]LGAGEGGEASVSPEKTSTTS KGKAKRDK TCOF1 c.791A>G p.K264R APAPGKVGDVTPQVKGGALPPAKRA[p. ALPPAKRARK LUAD K264R]RKPEEESESSEEGSESEEEAPAG TRS TCTE1 c.380G>T p.S127I PEHQQKVLNHLSPDLPLAVTANLID[p.S NLIDIENYWL,IENYWLRCCM,TANLIDIENY LUAD 127I]IENYWLRCCMHRWPVCHVAHH GGSWK TCTEX c.221C>T p.S74L HAVLKEELANAEYSPEEMPQLTKHL[p.S MPQLTKHLL,QLTKHLLENI,LTKHLLENIK CESC 1D2 74L]LENIKDKLKEMGFDRYKMVVQVVI GE TDO2 c.591G>C p.Q197H RVPYNRRHYRDNFKGEENELLLKSE[p. LLLKSEHEK,LKSEHEKTL,NELLLKSEH,HEKTLLELV,LKSE LUAD Q197H]HEKTLLELVEAWLERTPGLEPH HEKTLL,SEHEKTLLEL GFNF TDRD c.828G>T p.W276C CLAEYHLGDYGHAWNRCWVLDRVDT[p. DTCAVVMFI,RVDTCAVVM,CAVVMFIDF,VLDRVDTCAV,R KIRC 10 W276C]CAVVMFIDFGQLATIPVQSL VDTCAVVMF RSLDSD TDRD c.965C>T p.S322L SLDSDDFWTIPPLTQPFMLEKDILS[p.S3 MLEKDILSL,SLYEVVHRI,LYEVVHRIL,LEKDILSLY,DILSLYEV CRC 10 22L]LYEVVHRILKGKITGALNSAVTAPA V,KDILSLYEV,MLEKDILSLY,FMLEKDILSL,SLYEVVHRIL, S ILSLYEVVHR,KDILSLYEVV TEAD2 c.894_895 p.P298fs DVRQIYDKFPEKKGGLRELYDRGPP[p.P GQVLGGPEL,VLGGPELGPK,RELYDRGPPP STAD insC 298fs]PCLLPGQVLGGPELGPKW* TECTB c.85C>A p.L29I KAFVLLAIFAEASAKSCAPNKADVI[p.L2 VIIVFCYPK,APNKADVII,NKADVIIVF,IVFCYPKTI,KADVIIVF CRC 9I]IVFCYPKTIITKIPECPYGWEVHQLA CY,DVIIVFCYPK,APNKADVIIV,IVFCYPKTII TEDD c.498G>A p.M166I LLVLTAELWAPNMCHLQLMETFLIL[p. LMETFLILI,ILIMGSWLM,IMGSWLMQA,METFLILIM,FLILI CESC M1 M166I]IMGSWLMQAGFILYRPVSGYP MGSW,QLMETFLILI,FLILIMGSWL,LIMGSWLMQA,TFLILI WQDDD MGSW,ETFLILIMGS,LMETFLILIM,LILIMGSWLM TEKT5 c.1202G>A p.R401H LLERSIMAKEGPLKVAQTRLECRTR[p.R RTRHPNMEL,RTRHPNMELC,LECRTRHPNM,HPNMELCR CRC 401H]HPNMELCRDIPQLKLVNEVFTID DI DTL TET1 c.4415C>G p.T1472S AAVREIMENRYGQKGNAIRIEIVVY[p.T VVYSGKEGK,RIEIVVYSGK,IVVYSGKEGK TGCT 1472S]SGKEGKSSHGCPIAKWVLRRSS DEEK TEX15 c.4954G>C p.E1652Q ASSLQILQEETKVCLNILPLFVEAF[p.E16 FQRKQECSV CESC 52Q]QRKQECSVEQILISRELLVDQNLW NN TFE3 c.1444_144 p.G482fs SLKPEQLDIEEEGRPGAATFHVGGG[p. ALFSVPCCL,ALRCPSGPA,RMRPRLFPH,RLFPHPPMR,SAA STAD 5insG G482fs]TCPECSPSAAPCTALRCPSGPA PCTALR,LFPHPPMRL,LIRPHPSPG,PPGGPGRPL,CPVPTAG LSQRPPGGPGRPLPPGAGGHSDGGGG CL,SPALFSVPC,RPHPSPGTF,FPPRKGGPV,GPVRMRPRL,R GGGGRTVGGCPVPTAGCLRSPALFSVP PRLFPHPP,LRCPSGPAL,SQRPPGGPG,GCLRSPALF,LRSPA CCLQGQQPPQQLQHGRGVLIRPHPSP LFSV,QQLQHGRGV,LQHGRGVLI,MRLPCPGIL,HPSPGTFP GTFPPRKGGPVRMRPRLFPHPPMRLPC P,CLRSPALFSV,RLFPHPPMRL,ALRCPSGPAL,SQRPPGGPG PGILGEEEM* R,KGGPVRMRPR,RMRPRLFPHP,RPRLFPHPPM,HPSPGTF PPR,SPSAAPCTAL,RPPGGPGRPL,PPRKGGPVRM,GPVRM RPRLF,FPHPPMRLPC,AGCLRSPALF,LQGQQPPQQL,GQQ PPQQLQH,QQLQHGRGVL,IRPHPSPGTF,CPGILGEEEM TFG c.1145C>T p.A382V YQPRPGFTSLPGSTMTPPPSGPNPY[p. PYVRNRPPF,YVRNRPPFG,NPYVRNRPPF CLL A382V]VRNRPPFGQGYTQPGPGYR* TFPI2 c.616C>T p.R206C RTCDAFTYTGCGGNDNNFVSREDCK[p. CACAKALKK,KCACAKALK,CKCACAKAL,REDCKCACA,CAC GBM R206C]CACAKALKKKKKMPKLRFASRIR AKALKKK,KCACAKALKK KIR TFPI2 c.664C>T p.R222C NFVSREDCKRACAKALKKKKKMPKL[p. LCFASRIRK,CFASRIRKI,MPKLCFASR,KLCFASRIR,KKKMPK BLCA R222C]CFASRIRKIRKKQF* LCF,KKMPKLCFA,KLCFASRIRK,KKKMPKLCFA,KMPKLCFA SR,CFASRIRKIR,MPKLCFASRI,KKKKMPKLCF,KKMPKLCFAS TFPT c.755C>G p.S252C EALDSSWVSRGPDKLLPYPTLASPA[p.S YPTLASPAC BRCA 252C]CD* TGFBR c.722C>T p.S241L FGEVWRGKWRGEEVAVKIFSSREER[p. RLWFREAEI,LWFREAEIY,SSREERLWF,EERLWFREA,FSSR CRC 1 S241L]LWFREAEIYQTVMLRHENILGFI EERLW,SSREERLWFR,IFSSREERLW,KIFSSREERL,RLWFRE AAD AEIY,FSSREERLWF,REERLWFREA TGM6 c.1073de|C p.T358fs WNESWFARQDLGPSYNGWQVLDATP RVMCTWLTM,VMCTWLTMA,WLTMAPSCL,LTMAPSCLR, STAD [p.T358fs]RRRVKVCSGAAQPQSPPSA TMAPSCLRR,SVYTQTRRR,SLTSTSIRK,RLGDASAPR,TSLTS RVMCTWLTMAPSCLRRSTPTTSPGCGT TSIRK,TSIRKGPGK,RVKVCSGAA,SARVMCTWL,GTRMRAGSV, RMRAGSVYTQTRRRLGDASAPRRWAV RMRAGSVYT,QTRRRLGDA,ASAPRRWAV,SIRKGPGKR, TPAWTSLTSTSIRKGPGKRGRCTARR* QVLDATPRR,TTSPGCGTR,WTSLTSTSI,APSCLRRST,AVTP AWTSL,TPRRRVKVC,AQPQSPPSA,TRMRAGSVY,RRWAV TPAW,TPAWTSLTS,RVMCTWLTMA,LTMAPSCLRR,TSLTS TSIRK,STSIRKGPGK,TWLTMAPSCL,RVKVCSGAAQ,SARV MCTWLT,GTRMRAGSVY,RMRAGSVYTQ,RAGSVYTQTR,SVYTQT RRRL,QVLDATPRRR,WLTMAPSCLR,WTSLTSTSIR,TSIRKGPGKR, DASAPRRWAV,WAVTPAWTSL,RLGDASAPRR,QPQSPPSARV,APR RWAVTPA,TPAWTSLTST,RRVKVCSGAA, PQSPPSARVM,ARVMCTWLTM,AWTSLTSTSI,PPSARVMCTW THAD c.5822C>T p.S1941L RLLAFLEGKEGEDTLVLSVWDSYAE[p.S SVWDSYAEL,ELRQLTLPR,YAELRQLTL,SVWDSYAELR,SYA UCEC A 1941L]LRQLTLPRTEAAC* ELRQLTL,LSVWDSYAEL THAP c.860C>A p.S287Y EELNTNKESVIAIFVPAENSKPSVN[p.S2 VNYFISAQK,NSKPSVNYF,SVNYFISAQK,NSKPSVNYFI,KPS CRC 5 87Y]YFISAQKETTEMEDTDIEDSLYKDVD VNYFISA,AENSKPSVNY THEM c.50T>G p.L17R MLRSCAARLRTLGALC[p.L17R]RPPVG ALCRPPVGR,TLGALCRPPV,RLRTLGALCR,RPPVGRRLPG ACC 4 RRLPGSEPRPELRSFSSEEVI THRA c.1652A>G p.K551R YKAVQEKSSSPPPRKTSESRDKLGA[p.K ESRDKLGAR,GARGDFPTGK KIRC P3 551R]RGDFPTGKSSFSITREAQVNVRM DSF THSD c.268C>T p.R90C VCDWHSDLFQWEVSDWHHCVLVPYA LVPYACGEV,VLVPYACGEV GBM 7B [p.R90C]CGEVKPRTAECVTAQHGLQH RMVRCI THSD c.269G>A p.R90H VCDWHSDLFQWEVSDWHHCVLVPYA[p. LVPYAHGEV,YAHGEVKPR,VLVPYAHGEV CRC 7B R90H]HGEVKPRTAECVTAQHGLQH RMVRCI THSD c.376G>A p.E126K VTAQHGLQHRMVRCIQKLNRTVVAN[p. LNRTVVANK,VANKICEHF,NKICEHFAL,KLNRTVVANK,VV SKCM 7B E126K]KICEHFALQPPTEQACLIPCPR ANKICEHF DCVV TIAM1 c.739_740 p.G247 QLSTCQRANSLGDLYAQKNSGVTAN[p. TANMGPGSK,KNSGVTANM,ANMGPGSKF,VTANMGPGS TGCT GG>AT M G247M]MGPGSKFAGYCRNLVSDIPNL K,MGPGSKFAGY,QKNSGVTANM,TANMGPGSKF ANHKMP TIFAB c.129C>A p.D43E GPSAFANVPPRLQHDTSPLLLGRGQ[p. LLLGRGQEA,RGQEAHLQL,QEAHLQLQL,LLGRGQEAHL,E LUAD D43E]EAHLQLQLPRLSRRHLSLEPYLEK AHLQLQLPR,GQEAHLQLQL GS TIGD4 c.935C>T p.S312F VESFPAHPEVKNLKSIELAFFPSCL[p.S3 CLFSKCIAM,LFSKCIAMK,LAFFPSCLF,FPSCLFSKC,AFFPSC LUAD 12F]FSKCIAMKQGVIKSLKIKYRHCLIKK LFSK,CLFSKCIAMK,ELAFFPSCLF,SCLFSKCIAM,FPSCLFSKC I TIMD4 c.455_457 p.T152de| VRLNLQRASTTTHRTATTTTRRTTT[p.T RTTTSPTTTR,TTRRTTTSPT PRAD de|CAA 152de|]SPTTTRQMTTTPAALPTTVVTT PDLTTG TIMM c.249de|A p.K83fs GFLSGLLDNVKQELAKNKEMKESIK[p.K ESIKNSVTR,KESIKNSVT,EMKESIKNSV,KEMKESIKNS STAD 44 83fs]NSVTRPEG* TIMP3 c.596_597 p.A199fs YQSKHYACIRQKGGYCSWYRGWA SWYRGWAPPG STAD insC PP[p.A199fs]G* TINAG c.1207G>A p.E403K MQVREDFFHYKTGIYRHVTSTNKES[p. VTSTNKESK,STNKESKKY,KKYRKLQTH,VTSTNKESKK,STN MM E403K]KKYRKLQTHAVKLTGWGTLRG KESKKYR,HVTSTNKESK,KKYRKLQTHA AQGQK TLL1 c.158C>A p.P53Q CAGLDYDYTFDGNEEDKTETIDYKD[p.P KDQCKAAVF,YKDQCKAAVF LUAD 53Q]QCKAAVFWGDIALDDEDLNIFQID RT TLL1 c.458C>T p.T153M VKGKVPLQFSGQNEKNRVPRAATSR[p. RAATSRMER,VPRAATSRM,MERIWPGGV,RMERIWPGGV, CRC T153M]MERIWPGGVIPYVIGGNFTGS RVPRAATSRM,RAATSRMER,MERIWPGGVI QRAMF TLL2 c.2615C>T p.S872L LGRFCGSKKPDPTVASGSSMFLRFY[p.S FLRFYLDAS,SSMFLRFYL,FYLDASVQR,LRFYLDASV,SMFLR CRC 872L]LDASVQRKGFQAVHSTECGGRLK FYLDA,FLRFYLDASV,RFYLDASVQR AEV TLN2 c.623C>T p.S208L REQGVDENETLLLRRKFFYSDQNVD[p. FFYSDQNVDL UCEC S208L]LRDPVQLNLLYVQARDDILNGS HPVS TLR2 c.980A>T p.D327V RVIDPGKVETLTIRRLHIPRFYLFY[p.D32 YLFYVLSTL,YVLSTLYSL,VLSTLYSLT,FYLFYVLST,LFYVLSTLY, CLL 7V]VLSTLYSLTERVKRITVENSKVFLVP IPRFYLFYV,HIPRFYLFYV,YLFYVLSTLY,FYLFYVLSTL,FYVLS TLYSL,RFYLFYVLST,IPRFYLFYVL TLR4 c.1492T>G p.L498V LEVLKMAGNSFQENFLPDIFTELRN[p.L DIFTELRNV,FTELRNVTF,TELRNVTFL,LRNVTFLDL,IFTELR STAD 498V]VTFLDLSQCQLEQLSPTAFNSLSS NVTF,ELRNVTFLDL LQ TM6S c.44C>G p.S15W MSASAATGVFVLSL[p.S15W]WAIPVT VLSLWAIPV,VFVLSLWAI,WAIPVTYVF,SLWAIPVTY,GVFV BLCA F1 YVFNHLAAQHDSWTIVGVAA LSLWAI,FVLSLWAIPV,VLSLWAIPVT,SLWAIPVTYV,LWAIP VTYVF,LSLWAIPVTY TM9S c.272G>A p.R91H RLDSVESVLPYEYTAFDFCQASEGK[p.R HPSENLGQV,HPSENLGQVL,SEGKHPSENL CRC F2 91H]HPSENLGQVLFGERIEPSPYKFTFN K TMC5 c.826C>T p.R276C DYGSSETPKMTRGVLSRTSSIQPSF[p.R SIQPSFCHR,SSIQPSFCHR,RTSSIQPSFC SKCM 276C]CHRSDDPVGSLWGENDYPEGIE MASM TMCC c.329G>A p.R110H EQTSRDGNVAEYLKLVNNADKQQAG[p. QQAGHIKQV,HIKQVFEKK,QAGHIKQVF,AGHIKQVFEK,Q CRC 3 R110H]HIKQVFEKKNQKSAHSIAQLQ QAGHIKQVF,KQQAGHIKQV KKLEQ TMCO c.43_44de|TC p.S15fs MSTSSSSSWDNLLESLS[p.S15fs]QHS SLSQHSMEL,HSMELDTSK,MELDTSKFF,LESLSQHSM,SQH BLCA 2 MELDTSKFFGRD* SMELDT,SMELDTSKF,ELDTSKFFGR,ESLSQHSMEL,HSME LDTSKF,LLESLSQHSM,SQHSMELDTS,SMELDTSKFF,MEL DTSKFFG TME c.328G>C p.A110P AELLLLRGGIREGSLDLGHAPLGPY[p.A1 HAPLGPYPR,YPRGPHYDA,GPYPRGPHY,LGPYPRGPHY,YP KIRC M102 10P]PRGPHYDAGFTLLVPMFSLDGTEL RGPHYDAG QL TME c.879_881 p.P299de| FPPPALSLELQPPPPQRNSVPPPPP[p.P NSVPPPPPL,RNSVPPPPPL PRAD M121 de|GCC 299de|]LHGPPGRPHMSSPTRDPLDT* TME c.3955G>C p.E1319Q AHSPLEQHPQPPLPPPVPQPQEPQP[p. PQRLSPAPL,QPQEPQPQRL,EPQPQRLSPA,QPQRLSPAPL CESC M131 E1319Q]QRLSPAPLAHPSHPERASSAR HSSED TME c.1441C>T p.R481C EACDAVFVAGKESRGARGVRVDFWW[p. RVDFWWCRLR,FWWCRLRASL,GVRVDFWWCR, CRC M132A R481C]CRLRASLRLTVWAPLLPLRIEL WWCRLRASLR,WCRLRASLRL,VRVDFWWCRL TDTT TME c.1732C>T p.R578W GDSEEEEDDERRGRGCTLQYQHAMV[p. YQHAMVWVL,MVWVLTQFV,AMVWVLTQF,LQYQHAMV CRC M132 R578W]WVLTQFVAEAAGPGGHLA W,QYQHAMVWV,LQYQHAMVWV,YQHAMVWVLT,AM D HLLGSDWQ VWVLTQFV,MVWVLTQFVA,WVLTQFVAEA,QYQHAMV WVL,HAMVWVLTQF,TLQYQHAMVW TME c.618de|C p.P206fs SCRLQGDLGLCVAELELLSSWFSPP[p.P AMGSGQATV,STTPCTQGV,LSSWFSPPR,SMSPGPPCR,GS STAD M132 206fs]RWLPGGGSPWTSRRGPPWSST GASSFIR,SWFSPPRWL,TSRRGPPWS,GVREGTASG,KTRGE D TPCTQGVREGTASGKTRGEAMGSGQA AMGS,RGSGASSFI,SGKTRGEAM,SSWFSPPRW,WLPGGG TVTSMSPGPPCRGSGASSFIRHTGNPP* SPW,WTSRRGPPW,SGQATVTSM,CRGSGASSF,GEAMGS GQA,WLPGGGSPWT,LLSSWFSPPR,GVREGTASGK,TSMS PGPPCR,RWLPGGGSPW,KTRGEAMGSG,RGSGASSFIR,ST TPCTQGVR,SSTTPCTQGV,EAMGSGQATV,SPWTSRRGPP, LSSWFSPPRW,SSWFSPPRWL,ASGKTRGEAM,GEAMGSG QAT,GSGQATVTSM TME c.275C>T p.A92V FIGEFMKASVDVADLIGLNLVMSRN[p. LVMSRNVGK,SRNVGKGEY,GLNLVMSRNV,MSRNVGKGE GBM M147 A92V]VGKGEYKIMVAALGWATAELIM Y SRCI TME c.241C>T p.R81C SFVTFLQPVRETQIIMRIFLNPSNF[p.R8 PSNFCNFTR,FLNPSNFCNF,NPSNFCNFTR GBM M156 1C]CNFTRTCQDITGEFKMCSSCLVCES K TME c.425T>C p.L142P VYLVTEVYYNFMKPTQEMNISLVWC[p. ISLVWCPLV,SLVWCPLVL,VWCPLVLSF,NISLVWCPL,CPLV KIRC M161 L142P]PLVLSFAIKVLFSLTTHYFKVEDG LSFAI,NISLVWCPLV,ISLVWCPLVL,LVWCPLVLSF,MNISLV B GE WCPL TME c.944G>A p.R315Q KDYIMNPPLGKESIPLMTEATFDTL[p.R TLQLWLIIL,LQLWLIILL,EATFDTLQL,ATFDTLQLW,TLQLW UCEC M161 315Q]QLWLIILLCALRLAMMRSHLQAY LIILL,QLWLIILLCA,ATFDTLQLWL,TFDTLQLWLI,TEATFDTL B LNL QL,EATFDTLQLW TME c.993de|T p.G331fs LDNNAVNLFSSVLIALLLPTAAWGF[p.G GFGPGGELY,WGFGPGGEL,GELYFISTG,GFGPGGELYF,W BLCA M19 331fs]GPGGELYFISTG* GFGPGGELY TME c.419A>G p.D140G LFLIGAFLIIIGSLLLSGYISKGGA[p.D140 ISKGGAGRA,AGRAVPVLI,YISKGGAGR,SKGGAGRAV,YISK KIRC M230 G]GRAVPVLIIGILVFLPGFYHLRIAYY GGAGRA,AGRAVPVLII TME c.382C>G p.Q128E EMELEKVRMEFELTRLKYLHEKNQR[p. NQRERQHEV,YLHEKNQRER,NQRERQHEVV ACC M247 Q128E]ERQHEVVMEQLQRERQHEVV MEQLQQ TME c.467de|T p.F156fs VVSYFPDKVALLQRKVEENRNSLFF[p.F NSLFFSYCF,NRNSLFFSY,RNSLFFSYCF,ENRNSLFFSY STAD M41A 156fs]SYCF* TME c.690de|T p.F230fs RITPFLPNWFINITSPVINVPLKVF[p. NVPLKVFLL,LKVFLLVLF,VPLKVFLLV,NVPLKVFLLV,VPLKV STAD M41B F230fs]LLVLF* FLLVL TME c.259G>A p.G87S ASLDIWHCESTLSSDWQIATLALLL[p.G TLALLLSGA,ALLLSGAAI,LLLSGAAII,LLSGAAIIL,ALLLSGAAI KIRC M47 87S]SGAAIILIAFLVGLISICVGSRRRFY I,LLLSGAAIIL,LLSGAAIILI,TLALLLSGAA,SGAAIILIAF,LALLL SGAAI TME c.566G>A p.R189Q MELRFNTLAKCPHCKKISSVGSALP[p.R SVGSALPQR,LPQRRCCAY,SSVGSALPQR,ALPQRRCCAY,L CRC M55A 189Q]QRRCCAYITIGMICIFIGVGLTVG PQRRCCAYI TP TME c.231de|A p.K77fs LIVKMAGRCKSGFDPRHGSHNIKKK[p. IKKKPGTSL,NIKKKPGTSL,KKPGTSLQCY KIRP M60 K77fs]PGTSLQCYLN* TME c.188G>A p.R63Q DSLDGYHSFECGSIDPLTGSHYTCR[p.R HYTCRQSPR,RQSPRLLTN,SHYTCRQSPR,QSPRLLTNGY,R BRCA M71 63Q]QSPRLLTNGYYIWTEDSFLCDKDG QSPRLLTNG NI TME c.374G>A p.R125Q CNCCSQELETSFTYVDKNINLEQRN[p.R RNQSSPSAK,EQRNQSSPSA CRC M74 125Q]QSSPSAKGHNHPGELGWENPN EWSQE TME c.481_482 p.P161fs ERQPQEDLIVRCEAGEGECRTFMPP[p. RTFMPPPGH,MPPPGHPPR,RTFMPPPGHP,FMPPPGHPP STAD M79 insC P161fs]PGHPPRPH* R,GECRTFMPPP TMPR c.863C>T p.S288L IHEKYRSAAREYDIAVVQVSSRVTF[p.S2 QVSSRVTFL,FLDDIRQICL,VQVSSRVTFL,SSRVTFLDDI CRC SS11A 88L]LDDIRQICLPEASASFQPNLTVHITG TMPR c.775G>T p.G259C FTTYKNPARWTASFGVTIKPSKMKR[p. KMKRCLRRI,PSKMKRCLR,KPSKMKRCL,MKRCLRRII,CLRRI LUAD SS11E G259C]CLRRIIVHEKYKHPSHDYDISLAE IVHEK,KMKRCLRRII,SKMKRCLRRI,MKRCLRRIIV LS TMPR c.821G>A p.R274Q CFWKNKDPTQWIATFGATITPPAVK[p. KQNVRKIIL,TPPAVKQNV,KQNVRKIILH,ITPPAVKQNV,VK LUSC SS11F R274Q]QNVRKIILHENYHRETNENDIAL QNVRKIIL VQL TMPR c.47G>A p.R16Q MGENDPPAVEAPFSF[p.R16Q]QSLFG FSFQSLFGL,EAPFSFQSL,APFSFQSLF,VEAPFSFQS,QSLFGL UCEC SS3 LDDLKISPVAPDADAVAAQIL DDLK,VEAPFSFQSL,FQSLFGLDDL TMPR c.904G>A p.V302I ITSVYGCSRQEPVVEVLASGAIMAV[p.V AIMAVIWKK,GAIMAVIWK,IWKKGLHSY,SGAIMAVIW,IM GBM SS6 302I]IWKKGLHSYYDPFVLSVQPVVFQ AVIWKKGL,SGAIMAVIWK,GAIMAVIWKK,VIWKKGLHSY,I ACE WKKGLHSYY,LASGAIMAVI,ASGAIMAVIW TMTC c.1226C>G p.T409R RTQLPSTENIVVLSLSLLIIPFVPA[p. LIIPFVPAR,PFVPARNLF,FVPARNLFF,RNLFFYVGF,PARNL HNSC 2 T409R]RNLFFYVGFVIAERVLYIPSM FFYV,VPARNLFFY,IPFVPARNL,FVPARNLFFY,PFVPARNLF GFCLL F,RNLFFYVGFV,LIIPFVPA,VPARNLFFYV,IPFVPARNL,A RNLFFYVGF TMTC c.1831C>T p.R611C EAAEQSYRTAIKHRRKYPDCYYNLG[p.R CYYNLGCLY,CLYADLNRHV STAD 4 611C]CLYADLNRHVDALNAWRNATVL KPEH TMX3 c.451C>T p.R151C AHRVSGALIRPLPSQQMFEHMQKRH[p. HMQKRHCVF,MQKRHCVFF,KRHCVFFVY,EHMQKRHCV, LUAD R151C]CVFFVYVGGESPLKEKYIDAASE MQKRHCVFFV,HMQKRHCVFF,KRHCVFFVYV,QKRHCVFF LIV VY,EHMQKRHCVF,FEHMQKRHCV TNF c.139C>T p.L47F GGPQGSRRCLFLSLFSFLIVAGATT[p.L4 ATTFFCLLH,IVAGATTFF,TTFFCLLHF,LIVAGATTF,TFFCLLH DLBCL 7F]FFCLLHFGVIGPQREEFPRDLSLISP FGV,FLIVAGATTF,ATTFFCLLHF,FFCLLHFGVI, LIVAGATTFF TNFSF c.694G>A p.A232T SAGQRLGVHLHTEARARHAWQLTQG[p. WQLTQGTTV,QLTQGTTVL,GTTVLGLFR,TTVLG GBM 9 A232T]TTVLGLFRVTPEIPAGLPSPRS LFRV,TQGTTVLGL,TQGTTVLGLF,WQLTQGTTVL E* TNIP2 c.217C>G p.R73G LRARLAALEGDAAPSLVDALLEQVA[p.R ALLEQVAGF,QVAGFREQL,ALLEQVAGFR,QVAGFREQLR,E ACC 73G]GFREQLRRQEGGAAEAQMRQEIE QVAGFREQL,DALLEQVAGF RLT TNIP2 c.415G>A p.A139T QPQHEREKEVVLLRRSMAEGERARA[p. RARATSDVL,AEGERARAT,RARATSDVLC,GERARATSDV CRC A139T]TSDVLCRSLANETHQLRRTLTAT AHM TNK2 c.1894_189 p.P632fs PTRALPRPLHPTPVVDWDARPLPPP[p. RPLPPPARL,DARPLPPPAR STAD 5insC P632fs]ARL* TNKS2 c.1856_185 p.T619fs HEAAAKGKYEICKLLLQHGADPTKK[p.T PTKKKQGWK,KKQGWKYSF,PTKKKQGWKY,KKKQGWKYS CESC,CLL 7insA 619fs]KQGWKYSFGSC* F TNR c.2074C>A p.L692I SAVMNSQQSVPATMNARTELDSPRD[p. IMVTASSET,SPRDIMVTA,TELDSPRDI,DSPRDIMVTA,SPR LUAD L692I]IMVTASSETSISLIWTKASGPI DIMVTAS,TELDSPRDIM,IMVTASSETS DHYR TNS1 c.547C>T p.P183S GQPSQRRYVHYFSGLLSGSIKMNNK[p. KMNNKSLFL,KSLFLHHVI,SIKMNNKSL,SLFLHHVIM,IKMN TGCT P183S]SLFLHHVIMHGIPNFESKGGCRP NKSLF,KMNNKSLFLH,SIKMNNKSLF,KSLFLHHVIM,IKMN FLR NKSLFL,NKSLFLHHVI,SLFLHHVIMH TNXB c.2116_211 p.V706fs EEPPASACPGGCGPRELCRAGQCVC[p. RAGQCVCRGL ACC 7de|GT V706fs]RGLPRP* TOP2 c.2207G>T p.R736L NERSIPSMVDGLKPGQRKVLFTCFK[p.R KVLFTCFKL,KLNDKREVK,FTCFKLNDK,KLNDKREVKV,FTCF LUAD A 736L]LNDKREVKVAQLAGSVAEMSSY KLNDKR,RKVLFTCFKL HHGE TOP2 c.3595A>G p.K1199E FIEELEAVEAKEKQDEQVGLPGKGG[p.K KGGEAKGKK,GEAKGKKTQM THCA A 1199E]EAKGKKTQMAEVLPSPRGQRVI PRIT TOP2 c.1967G>A p.R656H IKYYKGLGTSTAKEAKEYFADMERH[p. DMERHHILF,MERHHILFR,RHHILFRYA,ADMERHHIL,FAD CRC B R656H]HILFRYAGPEDDAAITLAFSK MERHHI,YFADMERHHI,MERHHILFRY,DMERHHILFR,FA KKIDD DMERHHIL,ADMERHHILF TOPB c.4141de|A p.I1381fs ILDVLTGINVQQRRLALAAMRWRKK[p. FSQEEQRCY,LVGGRLFYM,RLFYMWISL,YLVILYLYL,YLYLK STAD P1 I1381fs]SSKDKNLALLREHLVGGRLFY RPHI,NLALLREHL,HLVGGRLFY,LVILYLYLK,FYMWISLEK,VI MWISLEKQASNAFFSQEEQRCYLVILYL LYLYLKR,VGGRLFYMW,CYLVILYLY,LYLKRPHIF,YLKRPHIF YLKRPHIFFLT* F,KSSKDKNLA,SSKDKNLAL,GGRLFYMWI,AFFSQEEQR,A MRWRKKSS,EQRCYLVIL,LKRPHIFFL,LEKQASNAF,REHLV GGRL,EKQASNAFF,KQASNQFFS,SQEEQRCYL,RCYLVILYL, EEQRCYLVI,QEEQRCYLV,NLALLREHLV,HLVGGRLFYM,Y MWISLEKQA,YLKRPHIFFL,AMRWRKKSSK,LFYMWISLEK, YLVILYLYLK,LVGGRLFYMW,CYLVILYLYL,LYLYLKRPFH,YLY LKRPHIF,LYLKRPHIFF,RWRKKSSKDK,SSKDKNLALL,EQRC YLVILY,RCYLVILYLY,LLREHLVGGR,NAFFSQEEQR,LVILYLY LKR,SLEKQASNAF,LEKQASNAFF,KSSKDKNLAL,KNLALLRE HL,REFILVGGRLF,GRLFYMVVISL,KQASNAFFSQ,ILYLYLKR PH,EEQRCYLVIL,QEEQRCYLVI TOR1 c.436G>A p.G146R PSDKVGRADAHLGSSSVALPKEASD[p. KEASDRTGA TGCT AIP2 G146R]RTGASQEPPTTDSQEAQSPGH SSAGQ TOR3 c.37T>C p.F13L MLRGPWRQLWLF[p.F13L]LLLLLPGAP RQLWLFLLL,QLWLFLLLL,FLLLLLPGA,PWRQLWLFL,LWLF ACC A EPRGASRPWEGTDEPGS LLLLL,RQLWLFLLLL,QLWLFLLLLL,PWRQLWLFLL,GPWRQ LWLFL TOX c.1061C>T p.S354L RASLVSKSYSEPVDVKTSQPPQLIN[p.S3 QLINLKPSV,LINLKPSVF,SQPPQLINL,SQPPQLINLK,QLINL CRC 54L]LKPSVFHGPSQAHSALYLSSHYHQ KPSVF QP TP53 c.1010G>T p.R337L TSSSPQPKKKPLDGEYFTLQIRGRE[p.R3 ELFEMFREL,LQIRGRELF,RGRELFEMF,TLQIRGREL,IRGREL LUAD,LUSC 37L]LFEMFRELNEALELKDAQAGKEPG FEM,RGRELFEMFR,TLQIRGRELF,IRGRELFEMF,RELFEMF GS REL TP53 c.173de|C p.P58fs SPLPSQAMDDLMLSPDDIEQWFTED[p. KLPECQRLL,SLPRKPTRA,RLLPPWPLH,LSLPRKPTR,PTRAA HNSC P58fs]QVQMKLPECQRLLPPWPLHQQ TVSV,RAATVSVWA,QMKLPECQR,TVSVWASCI,LPRKPTR LLHRRPLHQPPPGPCHLLSLPRKPTRAA AA,QQLLHRRPL,MKLPECQRL,QRLLPPWPL,TRAATVSVW, TVSVWASCILGQPSL* VSVWASCIL,WPLHQQLLH,TEDQVQMKL,SLPRKPTRAA,C QRLLPPWPL,LLSLPRKPTR,ATVSVWASCI,TVSVWASCIL,L PPWPLHQQL,LPRKPTRAAT,KPTRAATVSV,HQQLLHRRPL, QWFTEDQVQM,MKLPECQRLL,QQLLHRRPLH,HQPPPGP CHL,ASCILGQPSL,IEQWFTEDQV TP53 c.216de|C p.P72fs DDIEQWFTEDPGPDEAPRMPEAAPP[p. SLPRKPTRA,RMPEAAPPW,LSLPRKPTR,PTRAATVSV,RAA LUAD P72fs]WPLHQQLLHRRPLHQPPPGPC TVSVWA,TVSVWASCI,LPRKPTRAA,QQLLHRRPL,TRAATV HLLSLPRKPTRAATVSVWASCILGQPSL* SVW,VSVWASCIL,WPLHQQLLH,PEAAPPWPL,SLPRKPTR AA,LLSLPRKPTR,ATVSVWASCI,TVSVWASCIL,MPEAAPP WPL,APPWPLHQQL,LPRKPTRAAT,KPTRAATVSV,HQQLL HRRPL,QQLLHRRPLH,HQPPPGPCHL,ASCILGQPSL TP53 c.313G>T p.G105C PTPAAPAPAPSWPLSSSVPSQKTYQ[p. YQCSYGFRL,KTYQCSYGF,CSYGFRLGF,SQKTYQCSY, LUAD G105C]CSYGFRLGFLHSGTAKSVTCTYS TYQCSYGFR,KTYQCSYGFR,TYQCSYGFRL,PSQKTY PAL QCSY,QKTYQCSYGF,YQCSYGFRLG,CSYGFRLGFL TP53 c.323de|G p.G108fs AAPAPAPSWPLSSSVPSQKTYQGSY[p. YVSVWASCI,TYQGSYVSV,YQGSYVSVW,SYVSVWASC,KT BRCA G108fs]VSVWASCILGQPSL* YQGSYVS,VSVWASCIL,KTYQGSYVSV,YQGSYVSVWA,SQ KTYQGSYV,YVSVWASCIL,TYQGSYVSVW,SYVSVWASCI,A SCILGQPSL TP53 c.328de|C p.R110fs PAPAPSWPLSSSVPSQKTYQGSYGF[p. TYQGSYGFV,YQGSYGFVW,SYGFVWASC,YGFVWASCI,KTYQGSY BRCA R110fs]VWASCILGQPSL* GFV,YQGSYGFVWA,TYQGSYGFVW,SYGFVWASCI, YGFVWASCIL,ASCILGQPSL TP53 c.329G>T p.R110L PAPAPSWPLSSSVPSQKTYQGSYGF[p. YQGSYGFLL,FLLGFLHSG,TYQGSYGFL,SYGFLLGFL, HNSC,LUAD R110L]LLGFLHSGTAKSVTCTYSPALNK GSYGFLLGF,FLLGFLHSGT,KTYQGSYGFL,LLGFLHSGTA, MFC TYQGSYGFLL,YQGSYGFLLG,QGSYGFLLGF TP53 c.396G>C p.K132N YGFRLGFLHSGTAKSVTCTYSPALN[p.K ALNNMFCQL,NMFCQLAKT,TYSPALNNM,YSPALNNMF,A BLCA,BRCA 132N]NMFCQLAKTCPVQLWVDSTPPP LNNMFCQLA,TYSPALNNMF,CTYSPALNNM GTRV TP53 c.396G>T p.K132N YGFRLGFLHSGTAKSVTCTYSPALN[p.K ALNNMFCQL,NMFCQLAKT,TYSPALNNM,YSPALNNMF,A OV 132N]NMFCQLAKTCPVQLWVDSTPPP LNNMFCQLAT,YSPALNNMF,CTYSPALNNM GTRV TP53 c.421T>G p.C141G SGTAKSVTCTYSPALNKMFCQLAKT[p. CQLAKTGPV,KTGPVQLWV,AKTGPVQLW,QLAKTGPVQL, PRAD C141G]GPVQLWVDSTPPPGTRVRAM KMFCQLAKTG,LAKTGPVQLW AIYKQS TP53 c.422G>A p.C141Y SGTAKSVTCTYSPALNKMFCQLAKT[p. CQLAKTYPV,KTYPVQLWV,MFCQLAKTY,LAKTYPVQL,AKT BRCA C141Y]YPVQLWVDSTPPPGTRVRAMA YPVQLW,QLAKTYPVQL,KMFCQLAKTY,LAKTYPVQLW,YP IYKQS VQLWVDST TP53 c.427G>A p.V143M TAKSVTCTYSPALNKMFCQLAKTCP[p. KTCPMQLWV,CQLAKTCPM,AKTCPMQLW,MQLWVDST HNSC V143M]MQLWVDSTPPPGTRVRAMAI P,QLAKTCPMQL,FCQLAKTCPM,LAKTCPMQLW,MQLWV YKQSQH DSTPP,CPMQLWVDST TP53 c.451C>A p.P151T YSPALNKMFCQLAKTCPVQLWVDST[p. STTPPGTR,VQLWVDSTT,STTPPGTRVR,TPPGTRVRAM, HNSC P151T]TPPGTRVRAMAIYKQSQHMTE VQLWVDSTTP VVRRC TP53 c.455de|C p.P152fs SPALNKMFCQLAKTCPVQLWVDSTP[p. QLWVDSTPR,TPRPAPASA,RPAPASAPW,APWPSTSSH,W STAD P152fs]RPAPASAPWPSTSSHST* PSTSSHST,STPRPAPASA,TPRPAPASAP,APASAPWPST TP53 c.461G>T p.G154V ALNKMFCQLAKTCPVQLWVDSTPPP[p. WVDSTPPPV,VTRVRAMAI,DSTPPPVTR,STPPPVTRV,PPV LUAD G154V]VTRVRAMAIYKQSQHMTEVV TRVRAM,VTRVRAMAIY,DSTPPPVTRV,LWVDSTPPPV RRCPHH TP53 c.464C>A p.T155N LNKMFCQLAKTCPVQLWVDSTPPPG[p. STPPPGNRV,PPGNRVRAM,GNRVRAMAI,NRVRAMAIY,G GBM T155N]NRVRAMAIYKQSQHMTEVVR NRVRAMAIY,DSTPPPGNRV RCPHHE TP53 c.469G>T p.V157F KMFCQLAKTCPVQLWVDSTPPPGTR[p. RFRAMAIYK,GTRFRAMAI,TRFRAMAIY,PPGTRFRAM,TRF HNSQ,LIHC, V157F]FRAMAIYKQSQHMTEVVRRCP RAMAIYK,GTRFRAMAIY,RFRAMAIYKQ,STPPPGTRFR LUAD,LUSC,OV HHERC TP53 c.473G>A p.R158H MFCQLAKTCPVQLWVDSTPPPGTRV[p. RVHAMAIYK,GTRVHAMAI,PPGTRVHAM,TRVHAMAIY,G GBM,LIHC R158H]HAMAIYKQSQHMTEVVRRCP TRVHAMAIY HHERCS TP53 c.473G>T p.R158L MFCQLAKTCPVQLWVDSTPPPGTRV[p. RVLAMAIYK,GTRVLAMAI,TPPPGTRVL,PPGTRVLAM,TRV LUAD,LUSC R158L]LAMAIYKQSQHMTEVVRRCPH LAMAIY,GTRVLAMAIY HERCS TP53 c.475G>C p.A159P FCQLAKTCPVQLWVDSTPPPGTRVR[p. RVRPMAIYK,GTRVRPMAI,PPGTRVRPM,TRVRPMAIY,GT LUAD A159P]PMAIYKQSQHMTEVVRRCPHH RVRPMAIY,RVRPMAIYKQ ERCSD TP53 c.476C>T p.A159V FCQLAKTCPVQLWVDSTPPPGTRVR[p. RVRVMAIYK,GTRVRVMAI,RVMAIYKQS,TRVRVMAIY,GT BLCA,OV A159V]VMAIYKQSQHMTEVVRRCPH RVRVMAIY,RVRVMAIYKQ,VMAIYKQSQH HERCSD TP53 c.488A>G p.Y163C AKTCPVQLWVDSTPPPGTRVRAMAI[p. RVRAMAICK,AICKQSQHM,GTRVRAMAIC,RVRAMAICKQ, BRCA,HNSQ, Y163C]CKQSQHMTEVVRRCPHHERCS MAICKQSQHM LUAD,LUSC,OV DSDGL TP53 c.517G>A p.V173M DSTPPPGTRVRAMAIYKQSQHMTEV[p. MRRCPHHER,QSQHMTEVM,VMRRCPHHER,KQSQHMT BRCA,HNSC V173M]MRRCPHHERCSDSDGLAPPQ EVM HLIRVE TP53 c.517G>T p.V173L DSTPPPGTRVRAMAIYKQSQHMTEV[p. VLRRCPHHER,QSQHMTEVLR,KQSQHMTEVL BRCA,HNSC V173L]LRRCPHHERCSDSDGLAPPQH LIRVE TP53 c.523C>G p.R175G TPPPGTRVRAMAIYKQSQHMTEVVR[p. TEVVRGCPH,VVRGCPHHER LUSC R175G]GCPHHERCSDSDGLAPPQHLI RVEGN TP53 c.523C>T p.R175C TPPPGTRVRAMAIYKQSQHMTEVVR[p. TEVVRCCPH,VVRCCPHHER CRC R175C]CCPHHERCSDSDGLAPPQHLIR VEGN TP53 c.524G>A p.R175H TPPPGTRVRAMAIYKQSQHMTEVVR[p. TEVVRHCPH,VVRHCPHHER,SQHMTEVVRH BLCA,BRCA, R175H]HCPHHERCSDSDGLAPPQHLI CLL,CRC, RVEGN GBM,HNSC, LUAD,OV, PAAD,PRAD, STAD,UCS TP53 c.527G>A p.C176Y PPPGTRVRAMAIYKQSQHMTEVVRR[p. HMTEVVRRY,TEVVRRYPH,VVRRYPHHER,QHMTEVVRRY OV C176Y]YPHHERCSDSDGLAPPQHLIRV EGNL TP53 c.527G>T p.C176F PPPGTRVRAMAIYKQSQHMTEVVRR[p. HMTEVVRRF,TEVVRRFPH,VVRRFPHHER,QHMTEVVRRF BRCA,LUAD, C176F]FPHHERCSDSDGLAPPQHLIRV STAD EGNL TP53 c.535C>T p.H179Y GTRVRAMAIYKQSQHMTEVVRRCPH[p. VVRRCPHYE,EVVRRCPHY,VVRRCPHYER,TEVVRRCPHY,Y HNSC H179Y]YERCSDSDGLAPPQHLIRVEG ERCSDSDGL NLRVE TP53 c.536A>G p.H179R GTRVRAMAIYKQSQHMTEVVRRCPH[p.H EVVRRCPHR,VVRRCPHRER,RERCSDSDGL BRCA,GBM, 179R]RERCSDSDGLAPPQHLIRVEG HNSC,OV,UCS NLRVE TP53 c.536A>T p.H179L GTRVRAMAIYKQSQHMTEVVRRCPH[p. EVVRRCPHL,VVRRCPHLER,TEVVRRCPHL,LERCSDSDGL LUSC H179L]LERCSDSDGLAPPQHLIRVEG NLRVE TP53 c.572_574 p.P191de| SQHMTEVVRRCPHHERCSDSDGLAP[p. GLAPQHLIR,GLAPQHLIRV OV de|CTC P191de|]QHLIRVEGNLRVEYLDDRNT FRHSVVVP TP53 c.577C>T p.H193Y HMTEVVRRCPHHERCSDSDGLAPPQ[p. GLAPPQYLI,YLIRVEGNL,DSDGLAPPQY,GLAPPQYLIR,QYL BRCA H193Y]YLIRVEGNLRVEYLDDRNTFRH IRVEGNL,YLIRVEGNLR SVVV TP53 c.578A>G p.H193R HMTEVVRRCPHHERCSDSDGLAPPQ[p. GLAPPQRLI,RLIRVEGNL,RLIRVEGNLR BRCA,LIHC, H193R]RLIRVEGNLRVEYLDDRNTFRH OV,UCS SVVV TP53 c.578A>T p.H193L HMTEVVRRCPHHERCSDSDGLAPPQ[p. GLAPPQLLI,LLIRVEGNL,GLAPPQLLIR,LLIRVEGNLR BRCA,HNSC, H193L]LLIRVEGNLRVEYLDDRNTFRH LUSC SVVV TP53 c.581T>G p.L194R MTEVVRRCPHHERCSDSDGLAPPQH[p. GLAPPQHRI,RIRVEGNLR,APPQHRIRV,RIRVEGNLRV BRCA,OV L194R]RIRVEGNLRVEYLDDRNTFRHS VVVP TP53 c.584T>C p.I195T TEVVRRCPHHERCSDSDGLAPPQHL[p.I GLAPPQHLT,LTRVEGNLR,GLAPPQHLTR,LTRVEGNLRV,H BRCA,OV 195T]TRVEGNLRVEYLDDRNTFRHSVV LTRVEGNLR VPY TP53 c.587G>C p.R196P EVVRRCPHHERCSDSDGLAPPQHLI[p. HLIPVEGNL,APPQHLIPV,IPVEGNLRV,HLIPVEGNLR,LAPP HNSC R196P]PVEGNLRVEYLDDRNTFRHSVV QHLIPV VPYE TP53 c.596G>T p.G199V RRCPHHERCSDSDGLAPPQHLIRVE[p. HLIRVEVNL,LIRVEVNLR,EVNLRVEYL,VEVNLRVEY,LIRVEV BRCA G199V]VNLRVEYLDDRNTFRHSVVVPY NLRV,RVEVNLRVEY,HLIRVEVNLR,VEVNLRVEYL EPPE TP53 c.614A>G p.Y205C ERCSDSDGLAPPQHLIRVEGNLRVE[p.Y CLDDRNTFR,ECLDDRNTFR,VECLDDRNTF,VEGNLRVECL OV 205C]CLDDRNTFRHSVVVPYEPPEVGS DCT TP53 c.626_627 p.R209fs DSDGLAPPQHLIRVEGNLRVEYLDD[p. YLDDKHFST,VEYLDDKHF,RVEYLDDKHF BRCA de|GA R209fs]KHFST* TP53 c.641A>G p.H214R APPQHLIRVEGNLRVEYLDDRNTFR[p. NTFRRSVVV,FRRSVVVPY,TFRRSVVVPY,YLDDRNTFRR LUSC H214R]RSVVVPYEPPEVGSDCTTIHYN YMCN TP53 c.644G>T p.S215I PPQHLIRVEGNLRVEYLDDRNTFRH[p.S NTFRHIVVV,RNTFRHIVV,FRHIVVVPY,FRHIVVVPY LUAD 215I]IVVVPYEPPEVGSDCTTIHYNYMC NS TP53 c.645T>G p.S215R PPQHLIRVEGNLRVEYLDDRNTFRH[p.S NTFRHRVVV,RHRVVVPYE,FRHRVVVPY,TFRH OV 215R]RVVVPYEPPEVGSDCTTIHYNYM RVVVPY CNS TP53 c.646G>A p.V216M PQHLIRVEGNLRVEYLDDRNTFRHS[p.V NTFRHSMVV,DRNTFRHSM,FRHSMVVPY,MVVPYEPPEV, BRCA,GBM,OV 216M]MVVPYEPPEVGSDCTTIHYNYM TFRHSMVVPY CNSS TP53 c.659A>C p.Y220S IRVEGNLRVEYLDDRNTFRHSVVVP[p.Y VVPSEPPEV,VVVPSEPPEV BRCA 220S]SEPPEVGSDCTTIHYNYMCNSSC MGG TP53 c.659A>G p.Y220C IRVEGNLRVEYLDDRNTFRHSVVVP[p.Y VVPCEPPEV,VVVPCEPPEV BRCA,GBM, 220C]CEPPEVGSDCTTIHYNYMCNSSC HNSC,LUSC, MGG OV,UCEC TP53 c.701A>G p.Y234C RNTFRHSVVVPYEPPEVGSDCTTIH[p.Y CTTIHCNYM,TTIHCNYMC,CNYMCNSSCM BRCA,GBM, 234C]CNYMCNSSCMGGMNRRPILTIIT LUSC,OV LED TP53 c.706T>G p.Y236D TFRHSVVVPYEPPEVGSDCTTIHYN[p.Y NDMCNSSCM HNSC 236D]DMCNSSCMGGMNRRPILTIITLE DSS TP53 c.707A>G p.Y236C TFRHSVVVPYEPPEVGSDCTTIHYN[p.Y YNCMCNSSCM HNSC,OV 236C]CMCNSSCMGGMNRRPILTIITLE DSS TP53 c.711G>A p.M237I FRHSVVVPYEPPEVGSDCTTIHYNY[p. CTTIHYNYI,YNYICNSSCM HNSC M237I]ICNSSCMGGMNRRPILTIITLED SSG TP53 c.711G>C p.M237I FRHSVVVPYEPPEVGSDCTTIHYNY[p. CTTIHYNYI,YNYICNSSCM LUAD M237I]ICNSSCMGGMNRRPILTIITLED SSG TP53 c.713G>A p.C238Y RHSVVVPYEPPEVGSDCTTIHYNYM[p. TTIHYNYMY,YMYNSSCMG,YNYMYNSSC,CTTIHYNYMY,Y BRCA,GBM C238Y]YNSSCMGGMNRRPILTIITLEDS MYNSSCMGG,YNYMYNSSCM,IHYNYMYNSS,MYNSSCM SGN GGM TP53 c.713G>T p.C238F RHSVVVPYEPPEVGSDCTTIHYNYM[p. YMFNSSCMG,TTIHYNYMF,NYMFNSSCM,YNYMFNSSC,Y BRCA,GBM, C238F]FNSSCMGGMNRRPILTIITLEDS MFNSSCMGG,CTTIFIYNYMF,YNYMFNSSCM,IHYNYMFN HNSC SGN SS,MFNSSCMGGM TP53 c.722C>A p.S241Y VVVPYEPPEVGSDCTTIHYNYMCNS[p. NYMCNSYCM,HYNYMCNSY,SYCMGGMNR,NSYCMGGM UCS S241Y]YCMGGMNRRPILTIITLEDSSGN NR,IHYNYMCNSY,SYCMGGMNRR,YNYMCNSYCM,MCN LLG SYCMGGM TP53 c.722C>T p.S241F VVVPYEPPEVGSDCTTIHYNYMCNS[p. HYNYMCNSF,NYMCNSFCM,SFCMGGMNR,YMCNSFCM OV S241F]FCMGGMNRRPILTIITLEDSSGN G,NSFCMGGMNR,IHYNYMCNSF,SFCMGGMNRR,YNYM LLG CNSFCM TP53 c.723de|C p.S241fs VVPYEPPEVGSDCTTIHYNYMCNSS[p.S YMCNSSAWA,NYMCNSSAW,YNYMCNSSA,YMCNSSAW BRCA 241fs]AWAA* AA,HYNYMCNSSA,YNYMCNSSAW TP53 c.725G>T p.C242F VVPYEPPEVGSDCTTIHYNYMCNSS[p. SSFMGGMNR,YNYMCNSSF,NYMCNSSFM,SFMGGMNR CLL,HNSC, C242F]FMGGMNRRPILTIITLEDSSGNL R,YMCNSSFMG,FMGGMNRRPI,SSFMGGMNRR,HYNYM LUSC LGR CNSSF,NSSFMGGMNR,YNYMCNSSFM,YMCNSSFMGG, MCNSSFMGGM TP53 c.730G>T p.G244C PYEPPEVGSDCTTIHYNYMCNSSCM[p. YMCNSSCMC,SSCMCGMNR,CGMNRRPIL,SSCMCGMNR OV G244C]CGMNRRPILTIITLEDSSGNLLG R,NSSCMCGMNR,MCNSSCMCGM,CMCGMNRRPI RNS TP53 c.731G>A p.G244D PYEPPEVGSDCTTIHYNYMCNSSCM[p. SSCMDGMNR,DGMNRRPIL,NSSCMDGMNR,CMDGIVINRRPI CRC G244D]DGMNRRPILTIITLEDSSGNLLG RNS TP53 c.733G>A p.G245S YEPPEVGSDCTTIHYNYMCNSSCMG[p. SSCMGSMNR,GSMNRRPIL,MGSMNRRPI,CNSSCMGSM, CRC,GBM,HNSC, G245S]SMNRRPILTIITLEDSSGNLLGR SMNRRPILTI,SSCMGSMNRR,NSSCMGSMNR,MGSMNR OV,PRAD NSF RPIL,MCNSSCMGSM,CMGSMNRRPI TP53 c.734G>A p.G245D YEPPEVGSDCTTIHYNYMCNSSCMG[p. SSCMGDMNR,NSSCMGDMNR,CMGDMNRRPI OV G245D]DMNRRPILTIITLEDSSGNLLGR NSF TP53 c.734G>T p.G245V YEPPEVGSDCTTIHYNYMCNSSCMG[p. SSCMGVMNR,GVMNRRPIL,SCMGVMNRR,MGVMNRRP HNSC,LUSC,OV G245V]VMNRRPILTIITLEDSSGNLLGR I,CNSSCMGVM,YMCNSSCMGV,VMNRRPILTI,SSCMGVM NSF NRR,NSSCMGVMNR,MGVMNRRPIL,MCNSSCMGVM,C MGVMNRRPI TP53 c.742C>T p.R248W PEVGSDCTTIHYNYMCNSSCMGGMN[p. NWRPILTII,SSCMGGMNW,MGGMNWRPI,MNWRPILTI, BLCA,BRCA, R248W]WRPILTIITLEDSSGNLLGRN CMGGMNWRPI,GMNWRPILTI,SSCMGGMNWR,MNWR CLL,CRC, SFEVR PILTII,NSSCMGGMNW GBM,HNSC,OV, PAAD,UCEC TP53 c.743G>A p.R248Q PEVGSDCTTIHYNYMCNSSCMGGMN[p. MNQRPILTI,NQRPILTII,CMGGMNQRPI,GMNQRPILTI,SS BLCA,BRCA, R248Q]QRPILTIITLEDSSGNLLGRNS CMGGMNQR,NQRPILTIIT CLL,GBM,HNSC, FEVR OV,PRAD,STAD, UCEC,UCS TP53 c.743G>C p.R248P PEVGSDCTTIHYNYMCNSSCMGGMN[p. SCMGGMNPR,NPRPILTII,GMNPRPILTI,CMGGMNPRPI,S LUAD R248P]PRPILTIITLEDSSGNLLGRNSF SCMGGMNPR,NPRPILTIIT EVR TP53 c.745A>G p.R249G EVGSDCTTIHYNYMCNSSCMGGMNR[p. GPILTMTL,MNRGPILTI,GMNRGPILTI,CMGGMNRGPI,MN LUAD R249G]GPILTIITLEDSSGNLLGRNSFE RGPILTII VRV TP53 c.746G>T p.R249M EVGSDCTTIHYNYMCNSSCMGGMNR[p. MNRMPILTI,MPILTIITL,MGGMNRMPI,SCMGGMNRM,N LUAD R249M]MPILTIITLEDSSGNLLGRNSF RMPILTII,CMGGMNRMPI,GMNRMPILTI,RMPILTIITL,M EVRV NRMPILTII,SSCMGGMNRM,MPILTIITLE TP53 c.747G>T p.R249S EVGSDCTTIHYNYMCNSSCMGGMNR[p. MNRSPILTI,SPILTIITL,MGGMNRSPI,GMNRSPILTI,CMGG HNSC,LIHC, R249S]SPILTIITLEDSSGNLLGRNSFE MNRSPI,RSPILTIITL,MNRSPILTII LUAD VRV TP53 c.749C>T p.P250L VGSDCTTIHYNYMCNSSCMGGMNRR[p. RLILTIITL,GMNRRLILT,MNRRLILTI,GGMNRRLIL,GMNRR OV P250L]LILTIITLEDSSGNLLGRNSFEV LILTI,MNRRLILTII,RRLILTIITL RVC TP53 c.763A>T p.I255F TTIHYNYMCNSSCMGGMNRRPILTI[p.I RPILTIFTL,NRRPILTIF,FTLEDSSGNL,MNRRPILTIF,RRPILTI LUAD 255F]FTLEDSSGNLLGRNSFEVRVCACP FTL GR TP53 c.775G>T p.D259Y YNYMCNSSCMGGMNRRPILTIITLE[p. ILTIITLEY,LEYSSGNLL,PILTIITLEY,EYSSGNLLGR, OV D259Y]YSSGNLLGRNSFEVRVCACPGR LEYSSGNLLG DRRT TP53 c.785G>T p.G262V MCNSSCMGGMNRRPILTIITLEDSS[p. IITLEDSSV,DSSVNLLGR,LEDSSVNLL,VNLLGRNSF, HNSC G262V]VNLLGRNSFEVRVCACPGRDR MTLEDSSV,TLEDSSVNLL,SVNLLGRNSF RTEEE TP53 c.796G>A p.G266R SCMGGMNRRPILTIITLEDSSGNLL[p.G LLRRNSFEV,DSSGNLLRR,GNLLRRNSF,NLLRRNSFEV,LLRR OV 266R]RRNSFEVRVCACPGRDRRTEEEN NSFEVR,SGNLLRRNSF LRK TP53 c.797G>A p.G266E SCMGGMNRRPILTIITLEDSSGNLL[p.G LLERNSFEV,DSSGNLLER,GNLLERNSF,NLLERNSFEV,SGNL BRCA,HNSC 266E]ERNSFEVRVCACPGRDRRTEEEN LERNSF,LERNSFEVRV LRK TP53 c.797G>T p.G266V SCMGGMNRRPILTIITLEDSSGNLL[p.G LLVRNSFEV,LVRNSFEVR,GNLLVRNSF,NLLVRNSFEV,LVR OV 266V]VRNSFEVRVCACPGRDRRTEEEN NSFEVRV,SGNLLVRNSF,LEDSSGNLLV LRK TP53 c.800G>C p.R267P CMGGMNRRPILTIITLEDSSGNLLG[p.R LLGPNSFEV,GNLLGPNSF,NLLGPNSFEV,SGNLLGPNSF LUSC 267P]PNSFEVRVCACPGRDRRTEEENL RKK TP53 c.811G>A p.E271K MNRRPILTIITLEDSSGNLLGRNSF[p.E2 LLGRNSFKV,NLLGRNSFK,LGRNSFKVR,KVRVCACPG,NSFK BLCA,LUSC 71K]KVRVCACPGRDRRTEEENLRKKGE VRVCA,SFKVRVCAC,NLLGRNSFKV,GNLLGRNSFK,KVRVC PH ACPGR TP53 c.814G>A p.V272M NRRPILTIITLEDSSGNLLGRNSFE[p.V27 LLGRNSFEM,LGRNSFEMR,NSFEMRVCA,FEMRVCACP,NL BRCA,OV 2M]MRVCACPGRDRRTEEENLRKKGEP LGRNSFEM,EMRVCACPGR,FEMRVCACPG HH TP53 c.817C>T p.R273C RRPILTIITLEDSSGNLLGRNSFEV[p.R27 NSFEVCVCA,EVCVCACPGR,FEVCVCACPG BLCA,BRCA, 3C]CVCACPGRDRRTEEENLRKKGEPH CRC,HNSC,OV, HE STAD,UCEC TP53 c.818G>A p.R273H RRPILTIITLEDSSGNLLGRNSFEV[p.R27 NSFEVHVCA,LGRNSFEVH,EVHVCACPGR,HVCACPGRDR, BRCA,CLL, 3H]HVCACPGRDRRTEEENLRKKGEPH FEVHVCACPG CRC,GBM, HE HNSC,LUAD, OV,STAD, UCEC,UCS TP53 c.818G>T p.R273L RRPILTIITLEDSSGNLLGRNSFEV[p.R27 NSFEVLVCA,LGRNSFEVL,LLGRNSFEVL,EVLVCACPGR,FE LUAD,LUSC,OV 3L]LVCACPGRDRRTEEENLRKKGEPHH VLVCACPG E TP53 c.820G>T p.V274F RPILTIITLEDSSGNLLGRNSFEVR[p.V27 NSFEVRFCA,GRNSFEVRF,EVRFCACPGR,LGRNSFEVRF,FE LUAD 4F]FCACPGRDRRTEEENLRKKGEPHHE VRFCACPG L TP53 c.824G>A p.C275Y PILTIITLEDSSGNLLGRNSFEVRV[p.C27 RNSFEVRVY,YACPGRDRR,NSFEVRVYA,RVYACPGRDR,EV OV 5Y]YACPGRDRRTEEENLRKKGEPHHEL RVYACPGR,GRNSFEVRVY,FEVRVYACPG P TP53 c.824G>T p.C275F PILTIITLEDSSGNLLGRNSFEVRV[p.C27 FACPGRDRR,NSFEVRVFA,RNSFEVRVF,FEVRVFACP,RVF HNSC,LUAD 5F]FACPGRDRRTEEENLRKKGEPHHEL ACPGRDR,EVRVFACPGR,VFACPGRDRR,GRNSFEVRVF,FE P VRVFACPG TP53 c.830G>T p.C277F LTIITLEDSSGNLLGRNSFEVRVCA[p.C2 CAFPGRDRR,SFEVRVCAF,EVRVCAFPGR,NSFEVRVCAF,F LUAD 77F]FPGRDRRTEEENLRKKGEPHHELP EVRVCAFPG PG TP53 c.832C>T p.P278S TIITLEDSSGNLLGRNSFEVRVCAC[p.P2 CACSGRDRR,FEVRVCACS,EVRVCACSGR,FEVR HNSC 78S]SGRDRRTEEENLRKKGEPHHELPP VCACSG GS TP53 c.841G>A p.D281N TLEDSSGNLLGRNSFEVRVCACPGR[p. CACPGRNRR,RVCACPGRNR LUAD D281N]NRRTEEENLRKKGEPHHELPPG STKR TP53 c.844C>T p.R282W LEDSSGNLLGRNSFEVRVCACPGRD[p. CACPGRDWR,RDWRTEEENL BRCA,CRC,GBM, R282W]WRTEEENLRKKGEPHHELPPG HNSC,OV,STAD STKRA TP53 c.853G>A p.E285K SSGNLLGRNSFEVRVCACPGRDRRT[p. RTKEENLRK,RTKEENLRKK BLCA,CESC, E285K]KEENLRKKGEPHHELPPGSTKR HNSC,LUAD ALPN TP53 c.856G>A p.E286K SGNLLGRNSFEVRVCACPGRDRRTE[p. RTEKENLRK,RTEKENLRKK BRCA,STAD E286K]KENLRKKGEPHHELPPGSTKRAL PNN TP53 c.945_946 p.S315fs KGEPHHELPPGSTKRALPNNTSSSP[p.S KEETTGWRI,RIFHPSDPW,EETTGWRIF,RIFHPSDPWA,LP OV de|TC 315fs]AKEETTGWRIFHPSDPWA* NNTSSSPA,KEETTGWRIF,WRIFHPSDPW,EETTGWRIFH,S PAKEETTGW TP53R c.520de|C p.L174fs VLARMHDEDLIHGDLTTSNMLLKPP[p. SNMLLKPPW STAD K L174fs]WNS* TPO c.1193G>C p.S398T AACAPEPGIPGETRGPCFLAGDGRA[p. FLAGDGRAT,GRATEVPSL,TEVPSLTAL,TEVPSLTALH ACC S398T]TEVPSLTALHTLWLREHNRLAA ALKA TPO c.1672G>A p.E558K GGLDPLIRGLLARPAKLQVQDQLMN[p. QVQDQLMNK,KELTERLFV,LMNKELTERL,QLMNKELTER, LUAD E558K]KELTERLFVLSNSSTLDLASINLQ VQDQLMNKEL,MNKELTERLF,KELTERLFVL RG TPO c.2476G>A p.A826T ADGAHPPCHASARCRNTKGGFQCLC[p. CLCTDPYEL,FQCLCTDPY,GFQCLCTDPY CRC A826T]TDPYELGDDGRTCVDSGRLPR VTWIS TPPP c.89G>A p.R30K AKPAKAANRTPPKSPGDPSKDRAAK[p. KLSLESEGA,PSKDRAAKK,DRAAKKLSL KIRP R30K]KLSLESEGAGEGAAASPELSALEE AF TPR c.6464C>T p.S2155L EDRTVPSTPTLVVPHRTDGFAEAIH[p.S AEAIHLPQV,FAEAIHLPQV,AIHLPQVAGV,HLPQVAGVP CRC 2155L]LPQVAGVPRFRFGPPEDMPQT R,LPQVAGVPRF,AEAIHLPQVA SSSHS TPRX1 c.598T>C p.S200P NPGPIPGPNPGPIPGPISGPIPGPI[p.S2 GPIPGPIPV,IPGPIPVPI,IPVPIPGPI TGCT 00P]PVPIPGPIPGPISGPISGPNPGPIPG TPTE c.1268C>T p.S423L AQVKHLYNWNLPPRRILFIKHFIIY[p.S4 FIKHFIIYL,IIYLIPRYV,FIIYLIPRY,HFIIYLIPR,IYLIPRYV CRC,UCEC 23L]LIPRYVRDLKIQIEMEKKVVFSTISL R,IKHFIIYLI,FIKHFIIYLI,FIIYLIPRYV,YLIPRYVRDL,IIYL IPRYVR,LIPRYVRDLK,LFIKHFIIYL,KHFIIYLIPR,HFIIYLIPRY TPTE c.1623G>A p.M541I DNLHKQKARRIYPSDFAVEILFGEK[p.M VEILFGEKI,GEKITSSDV,GEKITSSDVV,VEILFGEKIT LUSC 541I]ITSSDVVAGSD* TPTE2 c.773G>A p.R258Q FPSSGRQSFYRNPIEEVVRFLDKKH[p.R KHQNHYRVY,QNHYRVYNL,KKHQNHYRV,FLDKKHQNHY, CRC 258Q]QNHYRVYNLCSERAYDPKHFHN HQNHYRVYNL,KKHQNHYRVY RVSR TRAF3 c.26C>T p.S9F MESSKKMD[p.S9F]FPGALQTNPPLKL MESSKKMDF,KKMDFPGAL,SSKKMDFPGA,SKKMDFPGAL CESC HTDRSAGTPVFVP TRAF7 c.32G>A p.R11H MSSGKSARYN[p.R11H]HFSGGPSNLP KSARYNHFS,SARYNHFSG,GKSARYNHF,KSARYNH DLBCL TPDVTTGTRMETTFGP FSG,SARYNHFSGG,SGKSARYNHF,NHFSGGPSNL TRAK1 c.1879G>A p.D627N DPRPGVVTKGFRTLDVDLDEVYCLN[p. DEVYCLNNF CRC D627N]NFEEDDTGDHISLPRLATSTPV QHPE TRAM c.121G>C p.E41Q HEFVLQNHADIVSCVAMVFLLGLMF[p. FLLGLMFQI,LMFQITAKA,FQITAKASI,GLMFQITAK,FLLGL BLCA 1 E41Q]QITAKASIIFVTLQYNVTLPATEE MFQIT,GLMFQITAKA,FQITAKASII,LGLMFQITAK,VFLLGL QA MFQI,MFQITAKASI,LMFQITAKAS,QITAKASIIF TRAM c.1033de|A p.R345fs LQRWVEDSNIQASCMKKKRSRSSKK[p. SKKEQKTEW,TEWEWKLQI,KEQKTEWEW,RSRSSKKEQK STAD 1L1 R345fs]EQKTEWEWKLQIE* TRAN c.2536G>A p.E846K YNISRRLSKLRVLPWSIHELYGDEI[p.E8 LYGDEIKDF,IKDFTQAEL,DEIKDFTQA,EIKDFTQAEL,KDFT UCEC K1 46K]KDFTQAELALLMKCINDPNSMFLT OAELAL,DEIKDFTQAE GD TRAPP c.399_400 p.K133fs WQNVLKAHSSVDWLIVIVENDAKKK[p. NLYCGQNKK,NQHPSPNLY,KQNQHPSPN,KQNQHPSPNL, GBM C10 insA K133fs]KQNQHPSPNLYCGQNKK* QNQHPSPNLY TRAPP c.1703G>A p.R568Q MNESPDPEPDCDILAVKTAQKLWAD[p. KLWADQISL,AQKLWADQI,KLWADQISLA,QISLAGSNIF,Q CRC C11 R568Q]QISLAGSNIFTIGVQDFVPFVQ KLWADQISL,DQISLAGSNI CKAK TRDN c.2190A>C p.*730Y PFTPADRPGESSGQANSPGQKQQGQ[p. YTHMYDPYK,MYDPYKCFK,QQGQYTHMY,KQQGQYTHM, KIRC *730Y]YTHMYDPYKCFKILKM* HMYDPYKCF,QKQQGQYTH,GQYTHMYDP,YKCFKILKM, DPYKCFKIL,HMYDPYKCFK,MYDPYKCFKI,KQQGQVTHMY, GQYTHMYDPY,GQKQQGQYTH,QKQQGQYTHM,THMY DPYKCF,SPGQKQQGQY TRIM23 c.1187G>A p.R396Q QQQFTEVADHIQLDASIPVTFTKDN[p. FTKDNQVHI,NQVHIGPKM,KDNQVHIGPK CRC R396Q]QVHIGPKMEIRVVTLGLDGAG KTTIL TRIM23 c.866G>A p.R289Q IVEDGIGMAHTEHVPGTAENARSCI[p. RSCIQAYFY,CIQAYFYDL,NARSCIQAY,ARSCIQAYF, CRC R289Q]QAYFYDLHETLCRQEEMALSVV IQAYFYDLH,ARSCIQAYFY,ENARSCIQAY,NARSCIQAYF, DAHV AENARSCIQA TRIM4 c.1193G>T p.R398L NVFTSGKHYWEVESRDSLEVAVGVC[p. LEVAVGVCL LUAD R398L]LEDVMGITDRSKMSPDVGIWAI YWSA TRIM42 c.379C>A p.Q127K TFHKGRLRSIHTSSKTALRTGSSDT[p.Q1 ALRTGSSDTK LUAD 27K]KVDEVKSIPANSHLVNHLNCPMCS RL TRIM48 c.278C>A p.A93D CFECIKTIQQRNLKTNIRLKKMASL[p.A9 RLKKMASLD,KMASLDRKA,RLKKMASLDR,MASLDRKASL, LUAD 3D]DRKASLWLFLSSEEQMCGIHRETKK KKMASLDRKA,ASLDRKASLW,LDRKASLWLF M TRIM61 c.294G>C p.K98N SLTEIAKQLQIRSKKRKRQEEKHVC[p.K9 NKHNQVLTF,RQEEKHVCNK,CNKHNQVLTF,KHNQVLTF CESC 8N]NKHNQVLTFFCQKDLELLCPRCSLS F T TRIM7 c.994C>A p.L332I MKNKVWNVSLKTFVLKGMLKKFKED[p. MLKKFKEDI,KFKEDIRGEL,MLKKFKEDIR LUSC L332I]IRGELEKEEKVELTLDPDTANPRL IL TRIM9 c.1009C>A p.R337S FEACLVAQCDALIDALNRRKAQLLA[p.R AQLLASVNK,SVNKEHEHK,RKAQLLASV,KAQLLASVN LUAD 337S]SVNKEHEFIKLKVVRDQISHCTVK K,ASVNKEHEHK,RRKAQLLASV LRQ TRIML1 c.1197C>A p.H399Q DLFSLIGLKIGDDYSLWVSSPLKGQ[p.H LKGQQVREPV LUAD 399Q]QVREPVCKVGVFLDYESGHIAFY NGT TRIO c.1981C>T p.R661W QTGECDPEEIYQAAHQLEDRIQDFV[p. RIQDFVWRV,FVWRVEQRK,DFVWRVEQR,WRVEQRKIL, CRC R661W]WRVEQRKILLDMSVSFHTHVK DFVWRVEQRK,WRVEQRKILL ELWTW TRIOBP c.3899A>G p.H1300R DLPPPRRLAQRQPGPQAQCSSGGRT[p. GGRTRSPGR,RTRSPGRAE,GGRTRSPGRA,RTRSPGRAEV ACC H1300R]RSPGRAEVERLFGQERRKSEA AGAFQ TRIP11 c.1622de|A p.K541fs DQLSKQQNEGDSIISKLKQDLNDEK[p.K KMIKWTLLK,EFINLKMIK,NLKMIKWTL,LKMIKWTLL,KREF STAD 541fs]REFINLKMIKWTLLKS* INLKM,REFINLKMI,DEKREFINL,NLKMIKWTLL,EKREFINL KM,KMIKWTLLKS TRIP12 c.5324T>C p.L1775P KLMAKAIMDFRLVDLPLGLPFYKWM[p. WMPRQETSL,KWMPRQETS,LPFYKWMPR,MPRQETS MM L1775P]PRQETSLTSHDLFDIDPVVARS LT,YKWMPRQET,KWMPRQETSL,GLPFYKWMPR,MPRQETS VYHL LTS,YKWMPRQETS TRMT c.731G>T p.S244I ALAARGFSELSTLEVLPQVYNVRTV[p.S VYNVRTVIL,QVYNVRTVI,PQVYNVRTVI,QVYNVRTVIL TGCT 61A 244I]ILPPPDLGTGTDGPAGSDTSPFRS GT TRPA1 c.162G>T p.K54N TEDFKESLKVVFEGSAYGLQNFNKQ[p. NFNKQNKLKR,LQNFNKQNKL CRC K54N]NKLKRCDDMDTFFLHYAAAEGQ IELM TRPA1 c.2017de|A p.T673fs DKSCRDYYIEYNFKYLQCPLEFTKK[p.T6 YMNRLQPST,RLQPSTQWY,LQPSTQWYK,LHRMLYMN STAD 73fs]HLHRMLYMNRLQPSTQWYKITA R,STQWYKITA,KKHLHRMLY,EFTKKHLHR,FTKKHLHRM, * LEFTKKHLH,KHLHRMLYM,HRMLYMNRL,QPSTQWYKI,MLYM NRLQPS,HLHRMLYMNR,RLQPSTQWYK,LQPSTQWYKI,K KHLHRMLYM,FTKKHLHRML,TKKHLHRMLY,RMLYMNRL QP,YMNRLQPSTQ,MNRLQPSTQW,CPLEFTKKHL TRPC5 c.1469C>T p.S490L PREEWEMWHPTLIAEALFAISNILS[p.S FAISNILSL,AISNILSLL,ISNILSLLR,SLLRLISLF,LSLLRLISL, CRC,UCEC 490L]LLRLISLFTANSHLGPLQISLGRML FAISNILSLL,ILSLLRLISL,LLRLISLFTA,AISNILSLLR,  L LFAISNILSL,LSLLRLISLF,ISNILSLLRL TRPM3 c.1285C>T p.R429W TRTQAQHLFIILMECMKKKELITVF[p.R KELITVFWM,WMGSEGHQDI,KKKELITVFW,KKELITVFW UCEC 429W]WMGSEGHQDIDLAILTALLKGA M,KELITVFWMG NASA TRPM3 c.892G>T p.G298W QTMSNPMSKLTVLNSMHSHFILADN[p. FILADNWTT,LADNWTTGK,ADNWTTGKY,SHFILADNW,L LUAD G298W]WTTGKYGAEVKLRRQLEKHIS ADNWTTGKY,ILADNWTTGK,WTTGKYGAEV,HSHFILADN LQKIN W TRPM6 c.2984G>A p.R995H IAKMTANMFYIVIIMAIVLLSFGVA[p.R LLSFGVAHK,SFGVAHKAI,AHKAILSPK,LSFGVAH CRC 995H]HKAILSPKEPPSWSLARDIVFEPY KA,VLLSFGVAH,LLSFGVAHKA,VLLSFGVAHK,V WM AHKAILSPK,LSFGVAHKAI TRPM7 c.2528G>A p.R843Q VRILDSNEGKNEMEIQMKSKKLPIT[p.R ITQKFYAFY,KSKKLPITQ,KLPITQKFY,KKLPITQKF,TQKFYAF CRC 843Q]QKFYAFYHAPIVKFWFNTLAYLG YH,QKFYAFYHA,LPITQKFYA,KLPITQKFYA,KSKKLPITQK,IT FLM QKFYAFYH,TQKFYAFYHA,KKLPITQKFY,PITQKFYAFY,LPIT QKFYAF,SKKLPITQKF,QKFYAFYHAP TRPM7 c.5584C>T p.R1862C PQDEPSDLNLQPGNSTKESESTNSV[p. SESTNSVCL,KESESTNSVC,SESTNSVCLM CRC R1862C]CLML* TRPM8 c.2295_229 p.H765fs VFYIAFLLLFAYVLLMDFHSVPHPP[p.H VLAGLCPLL,HSVPHPPRA,HPPRAGPVL,RAGPVLAGL,DFH STAD 6insC 765fs]RAGPVLAGLCPLL* SVPHPPR,VPHPPRAGPV,GPVLAGLCPL TRPS1 c.3373C>T p.R112 IEKYQYPLFGLPFVHNDFQSEADWL[p. WLWFWSKYK,FQSEADWLW,SEADWLWFW,LWFWSKYK CRC 5W R1125W]WFWSKYKLSVPGNPHYLSHV L,WLWFWSKYKL,EADWLWFWSK,DFQSEADWLW,FQSE PGLPNP ADWLWF,WFWSKYKLSV,DWLWFWSKYK,ADWLWFWSK Y,SEADWLWFWS TRPV2 c.1865_186 p.L627 KFTIGMGELAFQEQLHFRGMVLLLL[p.L MVLLLLAYV,VLLLLAYVL,RGMVLLLLA,GMVLLLLAY,GMVL CLL 7de|TGC de| 627de|]AYVLLTYILLLNMLIALMSETVN LLLAYV,MVLLLLAYVL,VLLLLAYVLL,RGMVLLLLAY SVATD TRPV3 c.653C>A p.A218E FAEENDILGRFINAEYTEEAYEGQT[p.A GQTELNIAI,ELNIAIERR,EAYEGQTEL,YEGQTELNI,AYEGQ KIRP 218E]ELNIAIERRQGDIAALLIAAGADV TELNI,QTELNIAIER,EEAYEGQTEL,YEGQTELNIA NA TRPV5 c.1475G>A p.R492H YFTRGFQMLGPFTIMIQKMIFGDLM[p. LMHFCWLMA,MHFCWLMAV,KMIFGDLMH,MIFGDLMH CRC R492H]HFCWLMAVVILGFASAFYIIFQT F,DLMHFCWLM,GDLMHFCWL,MIFGDLMHFC,LMHFCW EDP LMAV,KMIFGDLMHF,IFGDLMHFCW,HFCWLMAVVI,MH FCWLMAVV,GDLMHFCWLM TRRAP c.10543C>T p.R3515W THYYIKIARFMPRVEIVQKHNTAAR[p.R TAARWLYIR,AARWLYIRG,HNTAARWLY,NTAARWLYI,QK CRC 3515W]WLYIRGHNGKIYPYLVMNDAC HNTAARW,KHNTAARWL,WLYIRGHNGK,NTAARWLYIR, LTESR AARWLYIRGH,RWLYIRGHNG,KHNTAARWLY,VQKHNTA ARW,QKHNTAARWL TRRAP c.2917G>T p.A973S DCLKSANTEPYYRRQAWEVIKCFLV[p.A SMMSLEDNK,CFLVSMMSL,VIKCFLVSM,IKCFLVSMM,VS KICH 973S]SMMSLEDNKHALYQLLAHPNFT MMSLEDNK,EVIKCFLVSM,KCFLVSMMSL,SMMSLEDNKH, EKTI WEVIKCFLVS TSC1 c.1132G>T p.G378C CGMTTPPTSPGNVPPDLSHPYSKVF[p. KVFCTTAGG,YSKVFCTTA,SKVFCTTAG,KVFCTTAGGK, LUAD G378C]CTTAGGKGTPLGTPATSPPPAP HPYSKVFCTT LCHS TSC22 c.1255G>A p.A419T AQPSSTGAAASPATAATLPVGTGQN[p. NTSSVGAQL,GQNTSSVGA,NTSSVGAQLM ACC D2 A419T]TSSVGAQLMGASSQPSEAMAP RTGPA TSG101 c.794A>G p.K265R WRMKEEMDRAQAELNALKRTEEDLK[p. DLKRGHQKL,RGHQKLEEM THCA K265R]RGHQKLEEMVTRLDQEVAEV DKNIEL TSG101 c.826C>A p.R276S AELNALKRTEEDLKKGHQKLEEMVT[p. KLEEMVTSL,SLDQEVAEV,MVTSLDQEV,EMVTSLDQEV,TS LUAD R276S]SLDQEVAEVDKNIELLKKKDEEL LDQEVAEV,QKLEEMVTSL SSA TSHZ1 c.1503G>C p.K501N EDSLEKFEPSTLYPYLREEDLDDSP[p.K5 SPNGGLDIL LUAD 01N]NGGLDILKSLENTVSTAISKAQNG AP TSHZ1 c.2642G>T p.R881M QAQFASSLRETTEGKYIMSDLGPQE[p. MSDLGPQEM,QEMVHISKF,MSDLGPQEMV,IMSDLGPQE CRC R881M]MVHISKFTGLSMTTISHWLAN M,MVHISKFTGL,PQEMVHISKF,QEMVHISKFT VKYQL TSHZ2 c.664G>A p.A222T LYRQSSKMCGTVFTGASRFRCRQCS[p. RFRCRQCST,RCRQCSTAY,CSTAYDTLV,TAYDTLVEL,RQCS GBM A222T]TAYDTLVELTVHMNETGHYQD TAYDT,STAYDTLVEL,RFRCRQCSTA,FRCRQCSTAY,RQCST DNRKK AYDTL TSHZ3 c.2030G>T p.G677V EPIKMEASSDGGFRSQENSPSPPRD[p. RDVCKDGSPL LUAD G677V]VCKDGSPLAEPVENGKELVKPL ASSL TSKS c.1537G>A p.E513K CPSCQRLHKKILELERQALAKHVRA[p.E ALAKHVRAK,LAKHVRAKA,HVRAKALSS,RAKALSSTL,KALS BLCA 513K]KALSSTLRLAQDEALRAKNLLLTD STLRL,AKHVRAKAL,ALAKHVRAKA,QALAKHVRAK, KM HVRAKALSST,RAKALSSTLR,KALSSTLRLA,LAKHVRAKAL, VRAKALSSTL,AKALSSTLRL TSPAN4 c.274C>G p.L92V IGFVGCLGAIKENKCLLLTFFLLLL[p.L92 LTFFLLLLV,FLLLLVVFL,LLLLVVFLL,LLVVFLLEA,FFLLLLVVF, PRAD,CT V]VVFLLEATIAILFFAYTDKIDRYAQQ LLTFFLLLLV,LTFFLLLLVV,FLLLLVVFLL,LLLVVFLLEA,TFFLLL LVVF,FFLLLLVVFL TSSK1B c.901G>A p.E301K ARGSPSVAINKEGESSRGTEPLWTP[p.E GTEPLWTPK,RGTEPLWTPK UCEC 301K]KPGSDKKSATKLEPEGEAQPQAQ PET TTBK2 c.249T>G p.C83W KQVLKMEVAVLKKLQGKDHVCRFIG[p. WGRNDRFNY,VCRFIGWGR,FIGWGRNDR,IGWGRNDRF, KIRP C83W]WGRNDRFNYVVMQLQGRNLA HVCRFIGWGR,GWGRNDRFNY,RFIGWGRNDR,FIGWGR DLRRSQ NDRF TTC21A c.809C>A p.S270Y ESNIDACQILTVHELAREGNMTTVS[p.S NMTTVSYLK,TVSYLKTQK,EGNMTTVSY,GNMTTVSYL,GN CRC 270Y]YLKTQKATNHVRNLIKALETREPE MTTVSYLK,TTVSYLKTQK,REGNMTTVSY NP TTF1 c.1007 p.K336fs RPAVGLHGETAGIPAPAYKNKSKKK[p.K TLKDHRWAV,GLWKAVQLL,LVMIFQCPV,SLRKGSLRL,RLSKGH STAD de|A 336fs]RKSPITRNLRQWPCLRASRVHTL ECL,RASRVHTLK,TVQRRSLRK,WAVRLGLWK,LWKAV KDHRWAVRLGLWKAVQLLKGSRNPTV QLLK,RSLRKGSLR,RWAVRLGLW,IFQCPVRTL,RTLRAHSLI, QRRSLRKGSLRLSKGHECLVMIFQCPVR KNKSKKKRK,KKRKSPITR,KSPITRNLR,RNLRQWPCL,CLRAS TLRAHSLIQ* RVHT,RVHTLKDHR,HTLKDHRWA,AVRLGLWKA,GSRNPT VQR,NLRQWPCLR,QWPCLRASR,PTVQRRSLR,VMIFQCP VR,FQCPVRTLR,WPCLRASRV,NPTVQRRSL,SKKKRKSPI,LRA SRVHTL,RKSPITRNL,RQWPCLRAS,HRWAVRLGL,SKGH ECLVM,GHECLVMIF,VRTLRAHSL,CPVRTLRAH,KDHRWA VRL,RLSKGHECLV,CLVMIFQCPV,MIFQCPVRTL,CLRASRV HTL,LLKGSRNPTV,GLWKAVQLLK,RWAVRLGLWK,LVMIF QCPVR,KSKKKRKSPI,KKKRKSPITR,KRKSPITRNL,ITRNLRQ WPC,RNLRQWPCLR,RQWPCLRASR,HTLKDHRWAV, TLKDHRWAVR,AVRLGLWKAV,GSRNPTVQRR,RSLRKGSLRL, SLRKGSLRLS,RTLRAHSLIQ,IFQCPVRTLR,LSKGHECLVM, RVHTLKDHRW,HRWAVRLGLW,LRLSKGHECL,KG HECLVMIF,FQCPVRTLRA,SPITRNLRQW TTF1 c.1589A>G p.Q530R IKDRATSTIKRMYRDDLERFKEFKA[p.Q RGVAIKFGK,RFKEFKARG,KARGVAIKF,EFKARGVAI,KEFKA TGCT 530R]RGVAIKFGKFSVKENKQLEKNVE RGVA,RFKEFKARGV,EFKARGVAIK,KARGVAIKFG,KEFKAR DFL GVAI,FKARGVAIKF,RGVAIKFGKF TTF2 c.2281C>A p.R761S LDEAHNVKNPRVQTSIAVCKLQACA[p. KLQACASWA,LQACASWAV,CKLQACASW,SWAVTGTPI,KLQA LUAD R761S]SWAVTGTPIQNNLLDMYSLLKF CASWAV,LQACASWAVT,ASWAVTGTPI LRCS TTI1 c.2120G>A p.R707H CGYDSLQHLINQNSDYLVNGISLNL[p.R SLNLHHLAL,GISLNLHHL,LHHLALHPH,GISLNLHHLA,ISLNL STAD 707H]HHLALHPHTPKVLEVMLRNSDA HHLAL NLLP TTLL11 c.367_368 p.122_1 SELAARWEAEAVAAAKAAAKAEAEA[p. AAKAEAEAK,EAKATAETV,AEAEAKATA,AKATAETVA,AEA ACC insAGG 23insKA 122_123insKA]KATAETVAEQVRVDA KATAET,AAAKAEAEAK,AEAKATAETV CCA GAAGEPECKAGEEQPK TTLL7 c.2252G>A p.R751H LIKLDSVKQRKVLDIVKTSIRTVLP[p.R75 TVLPHIWKV,SIRTVLPHI,RTVLPHIWK,TSIRTVLPH,KTSIRT UCEC 1H]HIWKVPDVEEVNLYRIFNRVFNRLL VLPH,RTVLPHIWKV,TSIRTVLPHI,SIRTVLPHIW,LPHIWKV W PDV TUBA c.436C>T p.L146F EDGVVGLNYSCGNLGRRVNGELQLG[p. LQLGFLAII,ELQLGFLAI,VNGELQLGF,GELQLGFLA,RVNGE ACC,GCT 1C L146F]FLAIIN* LQLGF,GELQLGFLAI TUBA c.526_527 p.Q176fs SLLMERLSVDYGKKSKLEFAIYPAP[p.Q1 AIYPAPPGL,GLHGRGGAL,HGRGGALQL,LQLHPDHPH,FAI LUAD 3C insC 76fs]PGLHGRGGALQLHPDHPHDPGTF YPAPPGL,AIYPAPPGLH,LEFAIYPAPP,LHGRGGALQL * TUBA c.728G>A p.R243Q DIERPTYTNLNRLIGQIVSSITASL[p.R24 LQFDGALNV,SSITASLQF,ASLQFDGAL,SLQFDGALNV,ITA CRC 3D 3Q]QFDGALNVDLTEFQTNLVPYPRIHF SLQFDGA,VSSITASLQF,LQFDGALNVD P TUBB c.304G>A p.V102M TYHGDSHLQLERINVHHHEASGGRY[p. ASGGRYMPR,RYMPRAVLV,GGRYMPRAV,MPRAVLVDL, GBM P5 V102M]MPRAVLVDLEPGTMDSVRSG HEASGGRYM,GRYMPRAVL,YMPRAVLVDL,EASGGRYMP PFGQVL R,HHEASGGRYM TUBB c.356G>A p.R119H HEASGGRYVPRAVLVDLEPGTMDSV[p. MDSVHSGPF,HSGPFGQVL,SVHSGPFGQV,HSGPFGQVLR, UCS P5 R119H]HSGPFGQVLRPDNFIFGELRAR TMDSVHSGPF,VHSGPFGQVL TGVR TUBD1 c.599C>T p.A200V YGTGEVIVQNYNSILTLSHLYRSSD[p.A2 HLYRSSDVL,RSSDVLLLH,LYRSSDVLL,YRSSDVLLL,HLYRSS BRCA 00V]VLLLHENDAIHKICAKLMNIKQISFS DVLL,VLLLHENDAI,LYRSSDVLLL,SHLYRSSDVL TUFT1 c.1018G>A p.A340T KSQQRKVRQMIEQLQNSKAVIQSKD[p. TTIQELKEK,SKDTTIQEL,AVIQSKDTTI CRC A340T]TTIQELKEKIAYLEAENLEMHDR MEH TUFT1 c.303G>C p.L101F HSAGHSLASELVESHDGHEEIIKVY[p.L1 IIKVYFKGR,KVYFKGRSG,YFKGRSGDK,FKGRSGDKM,HEEIIKVYF, CESC 01F]FKGRSGDKMIHEKNINQLKSEVQY VYFKGRSGDK,EIIKVYFKGR IQ TWIST c.918T>A p.H306Q KKKHQEVQDQDPVFQGSDSSGYQSD[p. SSGYQSDQK CLL NB H306Q]QKKKKKKRKHSEEAEFTPPLK CSPKR TXND c.1028G>A p.R343Q LIKSVDWLLVFSLFFLISFIMYATI[p.R34 FIMYATIQT,IQTESIRWL,QTESIRWLI,YATIQTESI,IMYATIQ CRC C15 3Q]QTESIRWLIPGQEQEHVE* TE,IQTESIRWLI,IMYATIQTES,MYATIQTESI TXNL1 c.700C>T p.R234C AERSEPTQALELTEDDIKEDGIVPL[p.R2 GIVPLCYVK,IVPLCYVKF,DGIVPLCYV,KEDGIVPLCY,GIVPL UCEC 34C]CYVKFQNVNSVTIFVQSNQGEEET CYVKF TR TYRP1 c.1054_1 p.T352fs PEPQDVAQCLEVGLFDTPPFYSNST[p. TVSETQWKV,ESMTLLFEV,TLLFEVFTI,STVSETQWK,SMTL GBM 057de| T352fs]VSETQWKVTVTPRESMTLLFEVF LFEVF,EVFTIWLIY,QWKVTVTPR,MTLLFEVFT,TPRESMTLL, ACAA TIWLIYS* SETQWKVTV,TQWKVTVTP,LLFEVFTIW,FEVFTIWLI,MTL LFEVFTL,LLFEVFTIWL,STVSETQWKV,TQWKVTVTPR,ESM TLLFEVF,TLLFEVFTIW,LFEVFTIWLI,KVTVTPRESM,EVFTI WLIYS,TPRESMTLLF,RESMTLLFEV,FEVFTIWLIY,SETQWK VTVT,TPPFYSNSTV U2AF1 c.101C>A p.S34Y FGTEKDKVNCSFYFKIGACRHGDRC[p.S YRLHNKPTF,CYRLHNKPTF,GDRCYRLHNK,GACRHGDRCY LAML 34Y]YRLHNKPTFSQTIALLNIYRNPQNS S U2AF1 c.101C>T p.S34F FGTEKDKVNCSFYFKIGACRHGDRC[p.S FRLHNKPTF,CFRLHNKPTF,ACRHGDRCFR,GDRCFRLHNK, CESC,LAML, 34F]FRLHNKPTFSQTIALLNIYRNPQNS GACRHGDRCF LUAD,UCS S UBC c.2051de|G p.G684fs EDGRTLSDYNIQKESTLHLVLRLRG[p.G SLHFPFNKV,HLVLRLRGV,LLRFQQISL,VLRLRGVSK,GVSKF STAD 684fs]VSKFPLLRFQQISLHFPFNKVVAF PLLR,ISLHFPFNK,RFQQISLHF,QQISLHFPF,RLRGVSKFP,R GVSKFPLL,FPLLRFQQI,FPFNKVVAF,LRLRGVSKF,LRGVSK FPL,VSKFPLLRF,LHFPFNKVV,RLRGVSKFPL,SLHFPFNKVV, LVLRLRGVSK,QISLHFPFNK,KFPLLRFQQI,FQQISLHFPF,HF PFNKVVAF,RGVSKFPLLR,ISLHFPFNKV,VLRLRGVSKF,GVS KFPLLRF,LRFQQISLHF,LHFPFNKVVA,FPLLRFQQIS UBC c.572T>C p.I191T TLEVEPSDTIENVKAKIQDKEGIPP[p.I19 TSRGSSLQA,PPTSRGSSL,IPPTSRGSSL,IQDKEGIPPT PRAD 1T]TSRGSSLQASSWKMAVLFLTTTSRR S UBE2J2 c.577G>T p.G193W KQKQKAQDELSSRPQTLPLPDVVPD[p. VPDWETHLV,VVPDWETHLV,DVVPDWETHL,WETH LUAD G193W]WETHLVQNGIQLLNGHAPGA LVQNGI,LPLPDVVPDW VPNLAG UBE2M c.392G>A p.G131D LEGNVCLNILREDWKPVLTINSIIY[p.G1 NSIIYDLQY,SIIYDLQYLF,TINSIIYDL,IIYDLQYLF,IYDLQYLFL,I TGCT 31D]DLQYLFLEPNPEDPLNKEAAEVLQ IYDLQYLFL,SIIYDLQYLF,INSIIYDLQY,LTINSIIYDL,NSIIYDL NN QYL UBE2 c.257G>T p.R86I EEYPMAAPKVRFMTKIYHPNVDKLE[p. EIISLDILK,HPNVDKLEI,LEIISLDIL,HPNVDKLEII CRC NL R86I]IISLDILKDKWSPALQIRTVLLSIQA UBE2O c.3354_33 p.R1118fs YENSRCYNEMALIRVVQSMTQLVRR[p. SMTQLVRRA,TQLVRRAPR,LVRRAPRGL,MTQLVRRAPR KIRC 55insG R1118fs]APRGL* UBIAD1 c.289G>A p.A97T AYRSHGVLDPRLLVGCAVAVLAVHG[p. GTGNLVNTY,AVHGTGNLV,TGNLVNTYY,GTGNLVNTYY,V CRC A97T]TGNLVNTYYDFSKGIDHKKSDDR LAVHGTGNL,HGTGNLVNTY,LAVHGTGNLV TLV UBOX5 c.1250C>T p.S417L LPTTSEHTAKKMKATNEPSLTHMDC[p. HMDCLTGPL,LTGPLSHEQK,THMDCLTGPL BLCA S417L]LTGPLSHEQKLSQSLEIALASTLG SM UBQL c.1568de|C p.A523fs PIGPIVPFTPIGPIGPIGPTGPAAP[p.A52 GLLCPALHL,LLCPALHLV,ALHLVKPRV,ALVAPRGLL,VLHQ STAD N2 3fs]LAPPALVAPRGLLCPALHLVKPRVL NLDPT,MLHSCRIQK,SSSFSKWCR,SFSKWCRPW,APRGLLC HQNLDPTSSSFSKWCRPWLEQMLHSC PA,KPRVLHQNL,EQMLHSCRI,NLDPTSSSF,WCRPWLEQM, RIQKSDFSNNWNSSTQWGS* QKSDFSNNW,NNWNSSTQW,APLAPPALV,GLLCPALHLV, LLCPALHLVK,QMLHSCRIQK,TSSSFSKWCR,SFSKWCRPW L,KWCRPWLEQM,LAPPALVAPR,GPAAPLAPPA,APLAPPA LVA,APRGLLCPAL,IQKSDFSNNW,RGLLCPALHL,HQNLDP TSSS,QNLDPTSSSF,SSFSKWCRPW,LEQMLHSCRI,HSCRIQ KSDF,SNNWNSSTQW,DPTSSSFSKW UBR1 c.4939G>T p.G1647W KHPVLCLFCGAILCSQNICCQEIVN[p. WEEVGACIF,QEIVNWEEV,WEEVGACIFH LUAD G1647W]WEEVGACIFHALHCGAG VCIFLKIRE UBR4 c.8406de|C p.P2802fs TAENVNNGNPSPLEALLAGAEGFPP[p. LMQMTRPWL,TSHLMQMTR,CWTSHLMQM,FPPCWTSH STAD P2802fs]CWTSHLMQMTRPWLN* L,HLMQMTRPW,AEGFPPCWT,HLMQMTRPWL,WTSHL MQMTR,GFPPCWTSHL,FPPCWTSHLM,SHLMQMTRPW, AEGFPPCWTS UBR5 c.6360de|A p.K212 EVLPTKMSYAANLKNVMNMQNRQKK KNSPCCQKK,KLRVQNQGH,RVQNQGHLL,VQNQGHLLM, KICH 0fs [p.K2120fs]KGKNSPCCQKKLRVQNQG LRVQNQGHL,NQGHLLMIL,MQNRQKKKGK,KGKNSPCCQ HLLMILLHN* K,KLRVQNQGHL,RVQNQGHLLM,LRVQNQGHLL,VQNQG HLLMI,NQGHLLMILL UBR5 c.7551G>T p.R251 LDDTDDGDDNAPLFYQPGKRGFYTP[p. GFYTPSPGK,RGFYTPSPG,RGFYTPSPGK,SPGKNTEARL TGCT 7S R2517S]SPGKNTEARLNCFRNIGRILGL CLLQ UBXN7 c.827C>T p.A276V LDQVTGFLGEHGQLDGLSSSPPKKC[p. KKCVRSESL CLL A276V]VRSESLIDASEDSQLEAAIRASL QET UGP2 c.784G>C p.D262H ASFYNSGLLDTFIGEGKEYIFVSNI[p.D2 NIHNLGATV,IFVSNIHNL,IFVSNIHNL,FVSNIHNLGA, BLCA 62H]HNLGATVDLYILNHLMNPPNGKR HNLGATVDLY,KEYIFVSNIH CEF UGT1 c.10A>G p.T4A MAR[p.T4A]AGWTSPIPLCVSLLLTCGF ARAGWTSPI,AGWTSPIPL,MARAGWTSPI,RAGWTSPIPL KIRP A1 AEAGKLL UGT2 c.290de|A p.N97fs EIYRVPFGKERIEGVIKDFVLTWLE[p.N9 LLQPFGDSI,DFVLTWLEI,TWLEIDHLL,LEIDHLLQP,VLTWL CRC A1 7fs]IDHLLQPFGDSIRRWPK* EIDHL,HLLQPFGDSI,LEIDHLLQPF,KDFVLTWLEI,QPFGDSI RRW UGT2 c.1340G>T p.R447I STDLLNALKTVINDPLYKENIMKLS[p.R4 KENIMKLSI,IMKLSIIQH,YKENIMKLSI,KENIMKLSII TGCT B11 47I]IIQHDQPVKPLDRAVFWIEFVMPH KG UGT2 c.866C>A p.P289H FQFPHPFLPNIDFVGGLHCKPAKPL[p.P HCKPAKPLHK,KPAKPLHKEM GBM B28 289H]HKEMEEFVQSSGENGVVVFSLG SVIS UGT2 c.642G>A p.M214I FPPSYVPVVMSELTDQMTFMERVKN[p. RVKNIIYVL,TFMERVKNI,KNIIYVLYF,IIYVLYFDF,VKNIIYVL LUAD B7 M214I]IIYVLYFDFWFEIFDMKKWDQF Y,MERVKNIIY,FMERVKNII,FMERVKNIIY,RVKNIIYVLY,TF YSEV MERVKNII,NIIYVLYFDF,IIYVLYFDFW,MTFMERVKNI,MERV KNIIYV,VKNIIYVLYF UGT8 c.304G>A p.E102K FNSTTSDAFLQSKMRNIFSGRLTAI[p.E1 KLFDILDHY,FSGRLTAIK,SGRLTAIKL,TAIKLFDIL,GRLTAIKL CRC,UCEC 02K]KLFDILDHYTKNCDLMVGNHALIQ F,RLTAIKLFDI,KLFDILDHYT,IFSGRLTAIK,SGRLTAIKLF,IKLF GL DILDHY UHRF c.3990de|C p.I1330fs EIPVVVPMQIELLNSSITLKDDIPP[p.I13 HLQAPSPSL,SLWPWNMLC,IQHLQAPSP,LQAPSPSLW,AP STAD 1BP1 30fs]SIQHLQAPSPSLWPWNMLC* SPSLWPW,SPSLWPWNM,TLKDDIPPSI,SPSLWPWNML,IQHLQAPS PS,QHLQAPSPSL,HLQAPSPSLW,IPPSIQHLQA UMO c.1677G>A p.M559I CQCRTTRDATPSRAGRACEGDLVSP[p. LVSPIGGGL,SPIGGGLSA,CEGDLVSPI,SPIGGGLSAA TGCT DL1 M559I]IGGGLSAATGVTVPGLGTGTAA LGLE UNC9 c.1334_133 p.V445A LTMVAYGLVECVESKNPIRPHAPGQ[p. RPHAPGQAN TGCT 3A 5TC>CG V445A]ANQAEDEEIQTKM* UNC9 c.1492G>A p.V498M YHWWQAVAIFTVYLGSSLHMKAKLA[p. KLAMLLVTL,LAMLLVTLV,AMLLVTLVA,MLLVTLVAA,HMK CESC 3B1 V498M]MLLVTLVAAAVSYLRMEQKLR AKLAML,KAKLAMLLV,LHMKAKLAM,MKAKLAMLL,AKLA RGVAP MLLVT,KLAMLLVTLV,AMLLVTLVAA,MLLVTLVAAA,HMK AKLAMLL,KAKLAMLLVT,SLHMKAKLAM,LHMKAKLAML, MKAKLAMLLV,AKLAMLLVTL,LAMLLVTLVA UPK2 c.145de|C p.P49fs DFNISSLSGLLSPALTESLLVALPP[p.P49 SLLVALPPV,ALPPVTSQEA,ESLLVALPPV,LPPVTSQEAM STAD fs]VTSQEAMPH* UPK3A c.816_817 p.G272fs QITQEAVPKSLGASESSYTSVNRGP[p.G YTSVNRGPA KIRC insC 272fs]ATGQG* UQCR c.16T>G p.S6A MLSVA[p.S6A]ARSGPFAPVLSATSRGV SVAARSGPF,ARSGPFAPV,SVAARSGPFA, ACC FS1 AGALRPLVQ AARSGPFAPV,LSVAARSGPF,ARSGPFAPVL UQCR c.247A>G p.I83V QAVRRPLVASVGLNVPASVCYSHTD[p. VKVPDFSEY,SVCYSHTDVK,DVKVPDFSEY,SHTDVKVPDF KIRC FS1 I83V]VKVPDFSEYRRLEVLDSTKSSRESS E URGCP c.1916_191 p.G639fs HFLREMGQFYEAESCLVEAGRLPAG[p. HVWAAVCHR,RLPAGPEAF,HARPLGHRA,AARPTGETV,RS KICH 7insG G639fs]PEAFCPLPRLGLGAAADRAAS SRGLHAA,SSRGLHAAH,AVCHREELR,EAFCPLPRL,ETVKA GANRWEHAEHARPLGHRAPEGAARPT GGS,QVHTPQHHV,HTPQHHVWA,LPRLGLGAA,RPLGHR GETVKAGGSVNRRGARHGQVHTPQH APE,APEGAARPT,TPQHHVWAA,RAASGANRW,AEHARPL HVWAAVCHREELRSSRGLHAAHHSG* GH,RGARHGQVH,GQVHTPQHH,EELRSSRGL,GQVHTPQ HHV,AGRLPAGPEA,AARPTGETVK,TVKAGGSVNR,RSSRG LHAAH,SSRGLHAAHH,HTPQHHVWAA,LPRLGLGAAA,RP LGHRAPEG,TPQHHVWAAV,ELRSSRGLHA,GRLPAG PEAF,WEHAEHARPL,QVHTPQHHVW,WAAVCHREEL,REELRSS RGL,LRSSRGLHAA,PEAFCPLPRL,GETVKAGGSV,CPLPRLGLGA URI1 c.39_40 p.S13fs MEAPTVETPPDPSPP[p.S13fs]FGPGP GAAARGAGK,VARPGCGAA,SVARPGCGA,TPPDPSPPF,VA HNSC insC CPGSVARPGCGAAARGAGKGGH* RPGCGAAA,CGAAARGAGK,SVARPGCGAA USF1 c.155G>A p.R52Q DPTSVAIASIQSAATFPDPNVKYVF[p.R FQTENGGQV,QTENGGQVMY,FQTENGGQVM UCEC 52Q]QTENGGQVMYRVIQVSEGQLDG QTEG USH2A c.11156G>A p.R3719H NSTTVELYWSLPEKPNGLVSQYQLS[p.R YQLSHNGNL,QLSHNGNLL,LSHNGNLLF,SQYQLSHNG,SH GBM 3719H]HNGNLLFLGGSEEQNFTDKNLE NGNLLFL,YQLSHNGNLL,QYQLSHNGNL,QLSHNGNLLF,SQ PNSR YQLSHNGN,LSHNGNLLFL USH2A c.7107C>A p.F2369L KAHVRWEAPFRPNGLLTHSVLFTGI[p.F VLFTGILYV,SVLFTGILY,TGILYVDPV,HSVLFTGIL, CRC 2369L]LYVDPVGNNYTLLNVTKVMYSG HSVLFTGILY,SVLFTGILYV,FTGILYVDPV,LYVDPVGNNY EETN USP11 c.856G>A p.A286T VLDAALETGQLIIMETRKKDGTWPS[p. GTWPSTQLH,TWPSTQLHV,WPSTQLHVM,TWPSTQLHV CRC A286T]TQLHVMNNNMSEEDEDFKGQ M,TQLHVMNNNM PGICGL USP15 c.2344de|A p.K782fs KKRYFDENAAEDFEKHESVEYKPPK[p.K VEYKPPKNPL STAD 782fs]NPL* USP16 c.1364G>A p.R455Q DIPSGTSKHLQKKAKKQAKKQAKNQ[p. QAKNQQRQQK,QQRQQKIQGK,AKNQQRQQKI UCEC R455Q]QRQQKIQGKVLHLNDICTIDHP EDSE USP25 c.2618G>A p.R873H FKAIKLEYARLVKLAQEDTPPETDY[p.R8 ETDYHLHHV,HLHHVVVYF,YHLHHVVVY,TDYHLHHVV,ET UCEC 73H]HLHHVVVYFIQNQAPKKIIEKTLLE DYHLHHVV,HLHHVVVYFI,YHLHHVVVYF,DTPPETDYH Q L,TDYHLHHVVV USP25 c.3356G>A p.R1119Q EPPKLPSYSTHELCERFARIMLSLS[p.R1 MLSLSQTPA,RIMLSLSQT,IMLSLSQTP,IMLSLSQTPA CRC 119Q]QTPADGR* USP26 c.2582G>A p.R861Q TLKSGHYICDAYDFEKQIWFTYDDM[p. FTYDDMQVL,MQVLGIQEA,TYDDMQVLGI,MQVLGIQEAQ CRC R861Q]QVLGIQEAQMQEDRRCTGYIF FYMHN USP29 c.243C>A p.F81L NIRSVVLRHCKKRQSHLRLTLKNNV[p.F LLFIDKLSY,TLKNNVLLF,RLTLKNNVL,LKNNVLLFI,TLLKNNV CRC 81L]LLFIDKLSYRDAKQLNMFLDIIHQN LLFI,LLFIDKLSYR,LTLKNNVLLF,KNNVLLFIDK,VLLFIDKLSY, K LRLTLKNNVL,RLTLKNNVLL USP31 c.1171G>A p.D391N LTEMYYDGFHRSFCDTDDLETVHES[p. ETVHESNCI,TVHESNCIF,HESNCIFAF,TVHESNCIFA,ESNCI CRC D391N]NCIFAFETPEIFRPEGILSQRGIH FAFET,VHESNCIFAF LN USP33 c.107G>A p.R36Q LTLKVLPHFESLGKQEKIPNKMSAF[p.R KMSAFQNHC,SAFQNHCPH,MSAFQNHCPH,SAFQNHCP UCEC 36Q]QNHCPHLDSVGEITKEDLIQKSLG HL TC USP4 c.775C>G p.L259V STAPSRNFTTSPKSSASPYSSVSAS[p.L2 YSSVSASVI,PYSSVSASVI,SPYSSVSASV,YSSVSASVIA CESC 59V]VIANGDSTSTCGMHSSGVSRGGS GFS USP40 c.2552C>T p.S851L DSYTLKEAELKMGSSLGLCLGKAPS[p.S KAPSLSQLF,PSLSQLFLF,SLSQLFLFF,APSLSQLFL,GKAPSLS CRC 851L]LSQLFLFFAMGSDVQPGTEMEIV QL,SLSQLFLFFA,PSLSQLFLFF,KAPSLSQLFL,LGKAPSLSQL, VEE GKAPSLSQLF,APSLSQLFLF,LSQLFLFFAM USP42 c.2336G>C p.R779P SPAAESLEEPDAAAGLSSTKKAPPP[p.R STKKAPPPP,STKKAPPPPD ACC 779P]PDPGTPATKEGAWEAMAVAPEE USP46 c.410A>G p.Q137R LFDNYMQQDAHEFLNYLLNTIADIL[p. TIADILREEK,ILREEKKQEK,LLNTIADILR TGCT Q137R]REEKKQEKQNGKLKNGNMNE PAENNK UTP14A c.442G>A p.V148I EEIERIHREVAFNKTAQVLSKWDPV[p.V VLSKWDPVI,VLSKWDPVIL,ILKNRQAEQL,LSKWDPVILK CRC 148I]ILKNRQAEQLVFPLEKEEPAIAPIE H UTP3 c.226_228 p.E81de| SRAALAKGWNEVQSGDEEDGEEEEE[p. GEEEEEVLAL PRAD de|GAG E81de|]VLALDMDDEDDEDGGNAGEE EEEENADD UTS2R c.866C>A p.A289E VLLFWACFLPFWLWQLLAQYHQAPL[p. LEPRTARIV,APLEPRTARI,AQYHQAPLEP,HQAPLEPRTA,E KIRP A289E]EPRTARIVNYLTTCLTYGNSCA PRTARIVNY NPFL UXS1 c.298G>C p.V100L QKYPPVKFLSEKDRKRILITGGAGF[p.V1 LITGGAGFL,ILITGGAGFL,FLGSHLTDKL OV 00L]LGSHLTDKLMMDGHEVTVVDNFF TGR VARS c.151_152C p.P51S EAGEGPGWGGAHPRICLQPPPTSRT[p. TSRTSFPPP,RTSFPPPRL,SRTSFPPPR,SFPPPRLPAL,TSFP ACC C>AG P51S]SFPPPRLPALEQGPGGLWVWGA PPRLPA,QPPPTSRTSF TAVAQ VASH1 c.7de|G p.G3fs MPGG[p.G3fs]RRWLGVAAAVPLQRPL SLSTGVGYL,HLSLSAWKL,LSAWKLCSA,ATSESCSTI,YLWM STAD RPPPPLGSGVWRPAKEPQPREMRSQK RPPGK,ITQGHSSLK,VAAAVPLQR,GSGVWRPAK,SVGPQT RKGKRTCETEASPSLSTGVGYLWMRPP CPR,QTCPRSPYR,RWLGVAAAV,GGRRWLGVA,AVPLQRP GKGCGNTWPRSTPMERRWRNGSVGP LR,RSQKRKGKR,RWRNGSVGP,RSPYRVCLR,RVCLRSSRL,C QTCPRSPYRVCLRSSRLHLSLSAWKLCS LRSSRLHL,RSSRLHLSL,SSRLHLSLS,TGVGYLWMR,NTWPR ATSESCSTITQGHSSLKLRRADL* STPM,RPLRPPPPL,CPRSPYRVC,ERRWRNGSV,SLKLRRADL,R LHLSLSAW,GRRWLGVAA,RRWLGVAAA,LGVAAAVPL, AAVPLQRPL,LQRPLRPPP,AKEPQPREM,CETEASPSL,LSTG VGYLW,RSTPMERRW,RRWRNGSVG,PQTCPRSPY,SRLHL SLSA,TQGHSSLKL,TEASPSLST,WLGVAAAVPL,SLSAWKLC SA,RLHLSLSAWK,TITQGHSSLK,GVAAAVPLQR,STGVGYL WMR,GSVGPQTCPR,GGRRWLGVAA,LGSGVWRPAK,EM RSQKRKGK,KGKRTCETEA,GYLWMRPPGK,RSTPMERRW R,RWRNGSVGPQ,RVCLRSSRLH,CLRSSRLHLS,RSSRLHLSL S,SSRLHLSLSA,TWPRSTPMER,EASPSLSTGV,QTCP RSPYRV,STITQGHSSL,MPGGRRWLGV,RPPPPLGSGV,CPR SPYRVCL,MERRWRNGSV,SPSLSTGVGY,RRWLGVAAAV,AAAVP LQRPL,LQRPLRPPPP,SLSTGVGYLW,LSTGVGYLWM,GNT WPRSTPM,GPQTCPRSPY,YRVCLRSSRL,LRSSRLHLSL,SRL HLSLSAW,LHLSLSAWKL,SATSESCSTI VAV3 c.2053G>A p.E685K CVPKPVDYSCQPWYAGAMERLQAET[p. RLQAETKLI,KLINRVNST,AETKLINRV,KLINRVNSTY,AMER CRC E685K]KLINRVNSTYLVRHRTKESGEY LQAETK,MERLQAETKL AISI VCAN c.3374G>A p.R112 HSVSYPPGAVTEHKVKTDEVVTLTP[p. TLTPHIGPK,EVVTLTPHI,LTPHIGPKV,DEVVTLTPH,T CRC 5H R1125H]HIGPKVSLSPGPEQKYETEGSST LTPHIGPKV,VTLTPHIGPK,TPHIGPKVSL,DEVVTLTPHI TGF VCAN c.3923C>G p.S130 SSPPATQPTRPPTVEDKEAFGPQAL[p.S ALCTPQPPA,CTPQPPASTK,KEAFGPQALC CESC 8C 1308C]CTPQPPASTKFHPDINVYIIEVRE NK VEZF1 c.1063_106 p.355_3 ETSNQKQQQQQQQQQQQQQQQQQ HNVTSWPGK,QQQQQHNVT,QQQQHNVTS,QQQHNVTS STAD 4insACA 56insN QH[p.355_356insN]NVTSWPGKQVET W,NVTSWPGKQV,QQQQQQQHNV,QQQQQQHNVT,QQQQH LRLWEEAVKARKKEAA NVTSW,QQHNVTSWPG VHL c.115G>A p.G39S GAEEAGVEEYGPEEDGGEESGAEES[p. SPEESGPEEL KIRC G39S]SPEESGPEELGAEEEMEAGRPRP VLR VHL c.134C>T p.P45L VEEYGPEEDGGEESGAEESGPEESG[p.P PEESGLEEL,LEELGAEEEM,EESGPEESGL KIRC 45L]LEELGAEEEMEAGRPRPVLRSVNS RE VHL c.194C>T p.S65L PEESGPEELGAEEEMEAGRPRPVLR[p.S RPRPVLRLV,PVLRLVNSR,LVNSREPSQV,AGRPRPVLRL,RP KIRC 65L]LVNSREPSQVIFCNRSPRWLPVW RPVLRLVN LN VHL c.221T>A p.V74D GAEEEMEAGRPRPVLRSVNSREPSQ[p. PSQDIFCNR,DIFCNRSPR,SREPSQDIF,DIFCNRSPRV,NSRE KIRC V74D]DIFCNRSPRVVLPVWLNFDGEP PSQDIF QPYP VHL c.232A>G p.N78D EMEAGRPRPVLRSVNSREPSQVIFC[p. VIFCDRSPR,VIFCDRSPRV,QVIFCDRSPR KIRC N78D]DRSPRVVLPVWLNFDGEPQPYP TLPP VHL c.236G>C p.R79P MEAGRPRPVLRSVNSREPSQVIFCN[p. VIFCNPSPR,SQVIFCNPS,VIFCNPSPRV,QVIFCNPSPR,NPS KIRC R79P]PSPRVVLPVWLNFDGEPQPYPTL PRVVLPV,SQVIFCNPSP,FCNPSPRVVL PPG VHL c.245G>C p.R82P GRPRPVLRSVNSREPSQVIFCNRSP[p.R RSPPVVLPV,SPPVVLPVW,VIFCNRSPPV,RS KIRC 82P]PVVLPVWLNFDGEPQPYPTLPPGT PPVVLPVW GR VHL c.263G>T p.W88L LRSVNSREPSQVIFCNRSPRVVLPV[p.W VVLPVLLNF,SPRVVLPVL,RVVLPVLLNF,SPRVVLPVLL,RSP KIRC 88L]LLNFDGEPQPYPTLPPGTGRRIHSY RVVLPVL R VHL c.266T>A p.L89H RSVNSREPSQVIFCNRSPRVVLPVW[p.L VVLPVWHNF,RVVLPVWHNF,HNFDGEPQPY KIRC 89H]HNFDGEPQPYPTLPPGTGRRIHSY RG VHL c.266T>C p.L89P RSVNSREPSQVIFCNRSPRVVLPVW[p.L VVLPVWPNF,WPNFDGEPQ,RVVLPVWPNF KIRC 89P]PNFDGEPQPYPTLPPGTGRRIHSY RG VHL c.320G>C p.R107P RVVLPVWLNFDGEPQPYPTLPPGTG[p. GTGPRIHSY,TLPPGTGPR,TGPRIHSYR,LPPGTGPRI, KIRC R107P]PRIHSYRGHLWLFRDAGTHDGL TLPPGTGPRI,GTGPRIHSYR LVNQ VHL c.332G>A p.S111N PVWLNFDGEPQPYPTLPPGTGRRIH[p. NYRGHLWLF,TGRRIHNYR,RIHNYRGHL,GTGRRIHNY,IHN KIRC S111N]NYRGHLWLFRDAGTHDGLLVN YRGHLW,HNYRGHLWL,GTGRRIHNYR,HNYRGHLWLF,RI QTELF HNYRGHLW,NYRGHLWLFR,RRIHNYRGHL,IHNYRGHLWL VHL c.333C>A p.S111R PVWLNFDGEPQPYPTLPPGTGRRIH[p. RYRGHLWLF,TGRRIHRYR,RIHRYRGHL,GTGRRIHRY,IHRY KIRC S111R]RYRGHLWLFRDAGTHDGLLVN RGHLW,HRYRGHLWL,GTGRRIHRYR,HRYRGHLWLF,RIHR QTELF YRGHLW,RYRGHLWLFR,RRIHRYRGHL,IHRYRGHLWL VHL c.343C>A p.H115N NFDGEPQPYPTLPPGTGRRIHSYRG[p. SYRGNLWLF,RIHSYRGNL,HSYRGNLWL,IHSYRGNLW,HSY KIRC H115N]NLWLFRDAGTHDGLLVNQTEL RGNLWLF,RIHSYRGNLW,SYRGNLWLFR,RRIHSYRGNL,IH FVPSL SYRGNLWL VHL c.347de|T p.L116fs DGEPQPYPTLPPGTGRRIHSYRGHL[p.L LTDSLFLPI,TMGFWLTKL,YLCHLSMLT,SMLTDSLFL,HLSM KIRC 116fs]GSSEMQGHTMGFWLTKLNYLC LTDSL,SLFLPISHC,FLPISHCQC,HTMGFWLTK,FWLTKLNYL, HLSMLTDSLFLPISHCQCIL* NYLCHLSML,RGHLGSSEM,GFWLTKLNY,EMQGHTMGF, LSMLTDSLF,LNYLCHLSM,SSEMQGHTM,SEMQGHTMG, MQGHTMGFW,TKLNYLCHL,LPISHCQCI,KLNYLCHLSM,M LTDSLFLPI,FLPISHCQCI,HTMGFWLTKL,GFWLTKLNYL,RIHSY RGHLG,LTKLNYLCHL,MGFWLTKLNY,LPISHCQCIL,SEMQGHT MGF,HLSMLTDSLF,HSYRGHLGSS,YRGHLGSSEM,GSSEMQGHTM, MQGHTMGFWL,LNYLCHLSML,CHLSMLTDSL,LSMLTDSLFL VHL c.361G>T p.D121Y QPYPTLPPGTGRRIHSYRGHLWLFR[p. RYAGTHDGL,RGHLWLFRY,WLFRYAGTH,RYAGTH KIRC D121Y]YAGTHDGLLVNQTELFVPSLNV DGLL,RGHLWLFRYA,YRGHLWLFRY,FRYAGTHDGL DGQP VHL c.367de|G p.G123fs PTLPPGTGRRIHSYRGHLWLFRDAG[p. LTDSLFLPI,TMGFWLTKL,YLCHLSMLT,SMLTDSLFL,WLFR KIRC G123fs]HTMGFWLTKLNYLCHLSMLTD DAGHT,HLSMLTDSL,SLFLPISHC,FLPISHCQC,HTMGFWLTK, SLFLPISHCQCIL* FWLTKLNYL,NYLCHLSML,GFWLTKLNY,LSMLTDSLF,LF RDAGHTM,LNYLCHLSM,RDAGHTMGF,TKLNYLCHL,LPIS HCQCI,WLFRDAGHTM,KLNYLCHLSM,MLTDSLFLPI,FLPIS HCQCI,HTMGFWLTKL,GFWLTKLNYL,LTKLNYLCHL,MGF WLTKLNY,LPISHCQCIL,HLSMLTDSLF,FRDAGHTMGF,RD AGHTMGFW,LNYLCHLSML,CHLSMLTDSL,LSMLTDSLFL VHL c.383T>A p.L128H PGTGRRIHSYRGHLWLFRDAGTHDG[p. HLVNQTELF,GHLVNQTEL,HLVNQTELFV,GHLVNQTELF KIRC L128H]HLVNQTELFVPSLNVDGQPIFA NITL VHL c.405A>T p.L135F HSYRGHLWLFRDAGTHDGLLVNQTE[p. LVNQTEFFV,EFFVPSLNV,GLLVNQTEF,LLVNQTEFF,NQTE KIRC L135F]FFVPSLNVDGQPIFANITLPVYT FFVPS,LLVNQTEFFV,NQTEFFVPSL,GLLVNQTEFF,TEFFVP LKE SLNV VHL c.452T>C p.I151T DGLLVNQTELFVPSLNVDGQPIFAN[p.I FANTTLPVY,TTLPVYTLK,IFANTTLPV,NTTLPVYTL,QPIFAN KIRC 151T]TTLPVYTLKERCLQVVRSLVKPEN M,PIFANTTLPV,NTTLPVYTLK,IFANTTLPVY,GQPIFANTT YR L VHL c.458T>C p.L153P LLVNQTELFVPSLNVDGQPIFANIT[p.L1 IFANITPPV,ITPPVYTLK,FANITPPVY,NLIPPVYTL,PIFANITP KIRC 53P]PPVYTLKERCLQVVRSLVKPENYRR PV,NITPPVYTLK,IFANITPPVY,ANITPPVYTL L VHL c.472C>G p.L158V TELFVPSLNVDGQPIFANITLPVYT[p.L1 NITLPVYTV,ITLPVYTVK,TVKERCLQV,YTVKERCLQV,NITLP KIRC 58V]VKERCLQVVRSLVKPENYRRLDIVR VYTVK,TVKERCLQVV S VHL c.473T>C p.L158P TELFVPSLNVDGQPIFANITLPVYT[p.L1 ITLPVYTPK,TPKERCLQV,NITLPVYTPK,YTPKERCLQV,TPKE KIRC 58P]PKERCLQVVRSLVKPENYRRLDIVR RCLQVV S VHL c.492de|G p.Q164fs LNVDGQPIFANITLPVYTLKERCLQ[p.Q TLKERCLQL,KERCLQLSGA KIRC 164fs]LSGA* VHL c.506T>C p.L169P GQPIFANITLPVYTLKERCLQWRS[p.L1 CLQVVRSPV,LQVVRSPVK,RSPVKPENY,PVKPENYRR,CLQ KIRC 69P]PVKPENYRRLDIVRSLYEDLEDHPN VVRSPVK,VRSPVKPENY V VHL c.551T>C p.L184P KERCLQVVRSLVKPENYRRLDIVRS[p.L1 RLDIVRSPY,SPYEDLEDH,RRLDIVRSPY KIRC 84P]PYEDLEDHPNVQKDLERLTQERIA HQ VHL c.563T>C p.L188P LQVVRSLVKPENYRRLDIVRSLYED[p.L1 YEDPEDHPNV KIRC 88P]PEDHPNVQKDLERLTQERIAHQR MGD VLDLR c.692G>A p.R231H IPISWVCDDDADCSDQSDESLEQCG[p. LEQCGHQPV,EQCGHQPVI,SLEQCGHQPV,CGHQPVIHTK, BRCA R231H]HQPVIHTKCPASEIQCGSGECIH LEQCGHQPVI KKW VMP1 c.1105G>C p.E369Q AQRQKLHHKSEMGTPQGENWLSWM WLSWMFQKL,WMFQKLVVV,FQKLVVVMV,NWLSWMF LUAD F[p.E369Q]QKLVVVMVCYFILSIINSMA QK,SWMFQKLVV,MFQKLVVVM,WLSWMFQKLV,WMFQ QSYAKR KLVVVM,NWLSWMFQKL,SWMFQKLVVV,MFQKLVVVM V,ENWLSWMFQK,LSWMFQKLVV,QKLVVVMVCY VPRBP c.2405G>A p.R802Q ARLQKADVVAQSRISFPEKELLLLI[p.R8 LLLLIQNHL,LLLIQNHLI,LIQNHLISK,KELLLLIQN,LLLLIQNHL UCEC 02Q]QNHLISKGLGETATVLTKEADLPM L,IQNHLISKGL,LLIQNHLISK TA VPRB c.2817de|A p.K939fs CNGRKIRVLRQKSDHGAYSQSPAIK[p.K WTDIFLPHL,FLPHLRWTV,AIKNSWTDI,SWTDIFLPH,IKNS STAD P 939fs]NSWTDIFLPHLRWTV* WTDIF,WTDIFLPHLR,SWTDIFLPHL,IFLPHLRWTV,AIKNS WTDIF,SQSPAIKNSW,IKNSWTDIFL VPS c.8647de|T p.F2883fs ILGLDVLGNPFGLIREFSEGVEAFF[p.F2 NLTREPSRV,LTREPSRVL,EAFFMNLTR,MNLTREPSR,EPSR STAD 13A 883fs]MNLTREPSRVLKSLWKEWH* VLKSL,SEGVEAFFM,FMNLTREPS,VLKSLWKEW,VEAFFM NLT,FSEGVEAFFM,LTREPSRVLK,RVLKSLWKEW,PSRVLKS LWK,FMNLTREPSR,EGVEAFFMNL,REPSRVLKSL,EPSRVL KSLW VPS c.2075G>A p.R692Q IMGEKNSSNFMNTTNFQSLRPLPSI[p.R RPLPSIQIL,SLRPLPSIQI,RPLPSIQILV,IQILVDKINL UCEC 13B 692Q]QILVDKINLEHSVPMYAEQLVHV VSS VPS c.7723G>T p.G257 AQADCKLLECRNVTMQSVVKPFSIF[p. FSIFWQMAV,WQMAVSSDV,KPFSIFWQM,WQMAVSSD LUAD 13B 5W G2575W]WQMAVSSDVVEKLLDCTVIV VV,FSIFWQMAVS,VKPFSIFWQM,KPFSIFWQMA DSVFVN VPS c.4075G>T p.D135 SWYHKVPVVEIKGHLDSMNVSLNQE[p. SLNQEYLNL,YLNLLFRIL,EYLNLLFRI,MNVSLNQEY,NVSLN CRC 13C 9Y D1359Y]YLNLLFRILTENLCEGTEDLDK QEYL,NQEYLNLLF,SLNQEYLNLL,YLNLLFRILT,EYLNLLFRIL, VKPR SMNVSLNQEY,MNVSLNQEYL,LNQEYLNLLF,QEYLNLLFRI VWA2 c.950G>A p.G317D RTTCPGPCDSQPCQNGGTCVPEGLD[p. DDYQCLCPL,DYQCLCPLAF TGCT G317D]DYQCLCPLAFGGEANCALKLSL ECRV VWA3A c.2863G>A p.V955I LEKVLRRYVQRLQWLLSGSRRLFGT[p.V RLFGTILES,ILESKVCIL,GSRRLFGTI,SRRLFGTIL,ILES BRCA 955I]ILESKVCILLDTSGSMGPYLQQVKT KVCILL,RLFGTILESK,GSRRLFGTIL E VWA3B c.1670G>T p.R557L QFIQEQLKYKSKFNFVKFDGQAVAW[p. QAVAWLEQL,VAWLEQLAEV,GQAVAWLEQL LUAD R557L]LEQLAEVNEDNLEQAQSWIRDI KIGS VWA7 c.2375T>G p.V792G FSLTSNLSRAHLELNESAWGRLWLE[p. RLWLEGPDSA TGCT V792G]GPDSAAPDSVVMVTVTAGGR EANPVP VWF c.5160A>T p.K1720N LLDGSSSFPASYFDEMKSFAKAFIS[p.K1 FAKAFISNA,ISNANIGPR,KAFISNANI,KSFAKAFISN,SFAKA BRCA 720N]NANIGPRLTQVSVLQYGSITTIDV FISNA,FISNANIGPR,AKAFISNANI,ISNANIGPRL PW WAPAL c.1564 p.R522fs GFDDLSESEDDEDDDCQVERKTSKK[p. MIIPRTVSL,IIPRTVSLV,LTMQRTCLV,QLHHPPCSL,SLPQK STAD de|A R522fs]ELKQLHHPPCSLPQKAMIIPRT AMII,MQRTCLVCL,VSLVLTMQR,KAMIIPRTV,RTVSLVLTM, VSLVLTMQRTCLVCLKV* IPRTVSLVL,KQLHHPPCSL,AMIIPRTVSL,MIIPRTVSLV,V LTMQRTCLV,MQRTCLVCLK,TVSLVLTMQR,VERKTSKKEL, TMQRTCLVCL,KELKQLHHPP WASF3 c.913_914 p.P305fs EHEYRPPSASARHMALNRPQQPPPP[p. SSRLRDAPS,RPQQPPPPA,GLCTDGSSRL,SSRLRDAPSA,RP STAD insC P305fs]ASPSGPRGVPGLCTDGSSRLRD QQPPPPAS,SPSGPRGVPG APSADN* WASH c.523G>A p.G175S APREVVDPSGGRATLLESIRQAGGI[p.G RQAGGISKA,ISKAKLRSM,SIRQAGGISK,RQAGGISKAK,ISK GBM,KIRC, 3P 175S]SKAKLRSMKERKLEKKQQKEQEQ AKLRSMK PRAD,SKCM VRA WASH c.559C>G p.L187V ATLLESIRQAGGIGKAKLRSMKERK[p.L SMKERKVEK,RSMKERKVEK,SMKERKVEKK,KLRSMKERKV PRAD,TGCT 3P 187V]VEKKQQKEQEQVRATSQGGHL MSDLF WBP1 c.412_413insC p.P138fs LRFLSTFKPPAYEDVVHRPGTPPPP[p.P LYCGPRPPL,RPGTPPPPL,GPRPPLDCF STAD 138fs]LYCGPRPPLDCFQ* WBSC c.682C>T p.R228C LEEYVHKRYPGLVKVVRNQKREGLI[p.R REGLICARI,LICARIEGWK CRC R17 228C]CARIEGWKVATGQVTGFFDAHV EFTA WDFY3 c.5525de|T p.L1842fs FIFGVPASSGTWSSIHNVCTEAVF[p.L1 CTEAVFYYW,YYWECSAAC,EAVFYYWEC,FYYWECSAA, STAD 842fs]YYWECSAAC* AVFYYWECSA,HNVCTEAVFY,TEAVFYYWEC WDR17 c.832C>T p.P278S SESLSCITTFNLPSAAASVQCLAWV[p.P AWVSSAPGM,WVSSAPGMF,WVSSAPGMFI,AWVSSAPG CESC 278S]SSAPGMFITGDSQVGVLRIWNVS MF,LAWVSSAPGM,VQCLAWVSSA RTT WDR3 c.2521G>A p.E841K KSSELEESLLVLPFSYVPDILKLFN[p.E84 KLFNKFIQL,LKLFNKFIQL CRC 1K]KFIQLGSDVELICRCLFFLLRIHFGQ WDR34 c.178T>G p.W60G PGPLQDETLGVASVPSQWRAVQGIR[p. GETKSCQTA,AVQGIRGETK ACC W60G]GETKSCQTASIATASASAQARN HVDA WDR5 c.642de|C p.N214fs DGLCRIWDTASGQCLKTLIDDDNPP[p. TLIDDDNPPC STAD N214fs]CLL* WDR59 c.2509C>A p.R837S EHLSSPWGESSPEELRFGSLTYSDP[p.R LTYSDPSER LUAD 837S]SERERDQHDKNKRLLDPANTQQ FDDF WDR59 c.479de|A p.N160fs IKDTRKPTVALSAVAGASQVKWNKK[p. KMLTALPPA,MLTALPPAM,ALPPAMTAM,KWNKKMLTA, STAD N160fs]MLTALPPAMTAMCGYGIRGN PAMTAMCGY,TAMCGYGIR,MTAMCGYGI,WNKKMLTAL, PVQQWNI* SQVKWNKKM,KKMLTALPP,KMLTALPPAM,AMTAMCGY GI,MLTALPPAMT,ALPPAMTAMC,MTAMCGYGIR,KWNK KMLTAL,LTALPPAMTA,TALPPAMTAM,SQVKWNKKML,V KWNKKMLTA,KKMLTALPPA,PPAMTAMCGY WDR60 c.1235de|A p.Q412fs DGDDDESSNEPESREKLEELPLAQK[p.Q LLMQKMKGL,KMKGLASYL,KYKKFKELL,LAQKRKYKK,KFK STAD 412fs]RKYKKFKELLMQKMKGLASYL* ELLMQK,QKMKGLASY,RKYKKFKEL,MQKMKGLAS,AQKR KYKKF,YKKFKELLM,FKELLMQKM,LPLAQKRKY,LLMQKM KGLA,KYKKFKELLM,AQKRKYKKFK,KFKELLMQKM,MQK MKGLASY,LAQKRKYKKF,RKYKKFKELL,QKMKGLASYL WDR7 c.784de|G p.G262fs RVFDAGDYSLLCSGPSENGQTWTGG[p. FTNYLPVAF,VIFTNYLPV,YLPVAFQLV,FQLVIHSAV,VMWG STAD G262fs]TLSHQIKSSFGQKMGKVIFTNY RQLKI,QIKSSFGQK,SSFGQKMGK,AVMWGRQLK,NYLPVA LPVAFQLVIHSAVMWGRQLKI* FQL,MGKVIFTNY,LPVAFQLVI,LSHQIKSSF,QLVIHSAVM,G QTWTGGTL,HQIKSSFGQ,IKSSFGQKM,GQKMGKVIF,GKV IFTNYL,LVIHSAVMW,SAVMWGRQL,KVIFTNYLPV,VIFTN YLPVA,YLPVAFQLVI,HQIKSSFGAK,KSSFGQKMGK,KMGK VIFTNY,VIHSAVMWGR,SAVMWGRQLK,IFTNYLPVAF,NY LPVAFQLV,MGKVIFTNYL,AVMWGRQLKI,WTGGTLS HQI,SSFGQKMGKV,TLSHQIKSSF,FQLVIHSAVM,FGQKM GKVIF,VAFQLVIFISA,HSAVMWGRQL,LPVAFQLVIH WDR73 c.944_961 p.DGTR CLAISGFDGTVQVYDATSWDGTRSQ[p. TSWDGTRSQV KIRC de|ATGGAAC SQ315 DGTRSQ315de|]VEPLFTHRGHIFLDGN ACGGAG de| GMDPAPLVTTHTWHPCRPRTLLSATND CCAAG WDR75 c.860C>A p.P287Q SLLSGGRESVLVEWRDATEKNKEFL[p.P FLQRLGATI,KEFLQRLGA,EFLQRLGATI,KEFLQRLGAT, LUAD 287Q]QRLGATIEHISVSPAGDLFCTSHS LQRLGATIEH DN WDR78 c.330T>A p.N110K NQSRMAVSKTVLIPPELKTVEKPNP[p.N KTVEKPNPK,KIKTTQVFD,NPKIKTTQV,PKIKTTQVF,KIKTT CLL 110K]KIKTTQVFDINGTDVTPRPLYHPD QVFDI,NPKIKTTQVF PL WDR88 c.298G>T p.G100W KHQVPEKLIWGDQDPLSKIPFKILS[p.G KILSWHEHA,ILSWHEHAV,KIPFKILSW,FKILSWHEH,KILS LUAD 100W]WHEHAVSTCHFCVDDTKLLSGS WHEHAV,SKIPFKILSW,FKILSWHEHA YDCT WDTC1 c.861_862 p.M287fs RLRVLVATYVTFSPNGTELLVNMGG[p. NMGGGTGLF,VNMGGGTGL,NMGGGTGLFV,VNMGGGT STAD insG M287fs]GTGLFV* GLF WHSC c.1254_125 p.K418fs YIDKQPEEALSQAKKSVASKTEVKK[p.K PTTKICAEY,KICAEYSAR,RGGGLLTLK,GGGLLTLKY,CRGGG STAD 1L1 5insA 418fs]NPTTKICAEYSARTDQCRGGGLL LLTL,TTKICAEYSA,RGGGLLTLKY,EYSARTDQCR,NPTTKICA TLKY* EY,AEYSARTDQC WNK4 c.1816de|G p.G606fs CETDGYLSSSGFLDASDPALQPPGG[p. RLLPYPFHV,LLPYPFHVL,AMPQMQLQA,AMWEKGWDK,S STAD G606fs]CHPAWLSPISACPRLLPYPFHV ACPRLLPY,LQALAMWEK,PYPFHVLAL,HVLALEVTF,MQLQ LALEVTFPPGTAMPQMQLQALAMWE ALAMW,EVTFPPGTA,SPISACPRL,CPRLLPYPF,MPQMQL KGWDK* QAL,VTFPPGTAM,QMQLQALAM,HPAWLSPIS,LPYPFHVL A,LEVTFPPGT,ISACPRLLPY,RLLPYPFHVL,LLPYPFHVLA,A MPQMQLQAL,QLQALAMWEK,LAMWEKGWDK,WLSPIS ACPR,YPFHVLALEV,EVTFPPGTAM,HPAWLSPISA,SPISAC PRLL,LPYPFHVLAL,FPPGTAMPQM,MPQMQLQALA,LQP PGGCHPA,FHVLALEVTF,LEVTFPPGTA,PQMQLQALAM,Q MQLQALAMW,QPPGGCHPAW,QALAMWEKGW WNT1 c.500de|G p.W167fs SEGSIESCTCDYRRRGPGGPDWHWG[p. TLTSAASSA,GPDWHWGAA,WHWGAAATT,HWGAAATT STAD W167fs]AAATTLTSAASSAGSSWTPG L,AASSAGSSW,SAGSSWTPGR,TTLTSAASSA,GPD RRGGTCASS* WHWGAAA,SAASSAGSSW,WHWGAAATTL,AAATTLTSAA WNT11 c.1031G>A p.C344Y NPYTDRVVERCHCKYHWCCYVTCRR[p. CCYVTCRRY,RYERTVERY,YVTCRRYER,YERTVE OV C344Y]YERTVERYVCK* RYV,RRYERTVERY,CYVTCRRYER,YERTVERYVC WNT16 c.494de|G p.W165fs GNMTECSCDTTLQNGGSASEGWHWG[p. MMSSMACGS,SMACGSAES,MSSMACGSA,APMMSSMA STAD W165fs]AAPMMSSMACGSAESS* C,GAAPMMSSM,SEGWHWGAA,GWHWGAAPM,WHW GAAPMM,MMSSMACGSA,SASEGWHWGA,EGWHWGA APM,WGAAPMMSSM,GWHWGAAPMM,SMACGSAESS WNT5B c.979A>G p.K327E RLCNKTSEGMDGCELMCCGRGYNQF[p. RGYNQFES,QFESVQVER,NQFESVQVE,NQFESVQVER TGCT K327E]ESVQVERCHCKFHWCCFVRC KKCTEI WT1 c.1142_114 p.S381fs HTHGVFRGIQDVRRVPGVAPTLVRS[p. TLVRNHTSV,CTAGSTLVR,LVRSGRHLR,RSGRHLRPV,SGRH LAML 3insCGGTC S381fs]GRHLRPVRNAPSCVLTQAAIRD LRPVR,LVRNHTSVT,RNHTSVTSR,HTSVTSRTV,GFLVQTS ILSCPTYRCTAGSTLVRNHTSVTSRTVNE SK,RDILSCPTY,CVLTQAAIR,DILSCPTYR,RPVRNAPSC,TLVRSGRH GFLVQTSSKDTKGDIQV* L,VRNAPSCVL,TQAAIRDIL,YRCTAGSTL,TSRTVNEGF,LVQTSS KDTK,TYRCTAGSTL,RSGRHLRPVR,HLRPVRNAPS,STLVR NHTSV,TSRTVNEGFL,TLVRSGRHLR,RPVRNAPSCV,APSCV LTQAA,IRDILSCPTY,VTSRTVNEGF WWP2 c.1373G>C p.G458A EDPRTQGMIQEPALPPGWEMKYTSE[p. EMKYTSEAV,KYTSEAVRY,YTSEAVRYF,TSEAVRYFV,WEMKYTSEA, KIRC G458A]AVRYFVDHNTRTTTFKDPRPG YTSEAVRYFV,KYTSEAVRYF,MKYTSEAVRY,EMKY FESGT TSEAVR,WEMKYTSEAV,SEAVRYFVDH XAB2 c.2344G>A p.E782K SDLAPGQSGMDDMKLLEQRAEQLAA[p. EQLAAKAER,AKAERDQPL,EQRAEQLAAK BLCA E782K]KAERDQPLRAQSKILFVRSDA SREEL XDH c.1228C>T p.P410S MDHTFFPGYRKTLLSPEEILLSIEI[p.P41 ISYSREGEY,LSIEISYSR,SYSREGEYF,LLSIEISY,IEISYSREG,IS TGCT 0S]SYSREGEYFSAFKQASRREDDIAKVT YSREGEYF,LLSIEISYSR,EILLSIEISY,EEILLSIEIS XIRP2 c.7315G>A p.D2439N GKTGVLPPPTLPKPKLPKHIKDNKN[p.D KDNKNNFSPK,KHIKDNKNNF SKCM 2439N]NFSPKVELATSLSDMECKITTSK DQK XIRP2 c.9023T>A p.V3008E IPGWLISEDKREYAVHIAMENNLEK[p.V KEKEEITHI CLL 3008E]EKEEITHIKTQAEDMLVSYENIIQ TA XKR6 c.803G>A p.R268Q SVIHLLQMGQVWRYIRTMYLGIQSQ[p. MYLGIQSQQR,QQRKEHQRRF CRC R268Q]QRKEHQRRFYWAMMYEYAD VNMLRLL XPO1 c.1711G>A p.E571K QYPRFLRAHWKFLKTWNKLFEFMH[p. KLFEFMHKT,FMHKTHDGV,KTHDGVQDM,KLFEFMHKTH, BRCA,CLL E571K]KTHDGVQDMACDTFIKIAQKC VNKLFEFMHK,KTHDGVQDMA,EFMHKTHDGV,FMHKTH RRHFV DGVQ,HKTHDGVQDM XPOT c.1621C>T p.R541W EPQHIPCVLMAFLDHRGLRHSSAKV[p. KVWSRTAYL,HSSAKVWSR,VWSRTAYLF,SAKVWSRTA,W CRC R541W]WSRTAYLFSRFVKSLNKQMNP SRTAYLFS,AKVWSRTAY,LRHSSAKVW,KVWSRTAYLF,SAKVWS FIEDI RTAY,WSRTAYLFSR,GLRHSSAKVW,AKVWSRTAYL XYLB c.260C>T p.S87F TSPVLMWVQALDIILEKMKASGFDF[p. FQVLALSGA,MKASGFDFF,SGFDFFQVL,FDFFQVLAL,KAS BLCA S87F]FQVLALSGAGQQHGSIYWKAGA GFDFFQV,KMKASGFDFF,FQVLALSGAG QQAL XYLT2 c.1578de|C p.Y526fs RKFESTVNQEVLEILDFHLYGSYPP[p.Y5 HLYGSYPPA,RLMAPVGSV,SLLTQPSPA,LMAPVGSVM,CIS STAD 26fs]ARQPSRPTGRTPTTRLMAPVGSV MTTISR,RTPTTRLMA,TTRLMAPVG,ASACTMPPL,ISMTTI MSCSLLTQPSPASACTMPPLLHPQWA SRA,LYGSYPPAR,PTTRLMAPV,HSAGLSPGA,RPTGRTPTT, PHSAGLSPGACRPACTCISMTTISRATW* HPQWAPHSA,SPGACRPAC,RPACTCISM,LLHPQWAPH,G SVMSCSLL,MTTISRATW,MPPLLHPQW,RLMAPVGSVM,L LTQPSPASA,GLSPGACRPA,HLYGSYPPAR,TMPPLLHPQW, TGRTPTTRLM,ASACTMPPLL,SYPPARQPSR,TCISMTTISR, TPTTRLMAPV,QPSPASACTM,HPQWAPHSAG,APHSAGLS PG,RPACTCISMT,FHLYGSYPPA,PQWAPHSAGL,SMTTISR ATW,MPPLLHPQWA YBX1 c.749C>T p.P250L GAGEQGRPVRQNMYRGYRPRFRRGP[p. RFRRGPLRQ,RPRFRRGPL,RPRFRRGPLR,RFRRGPLRQR KIRP P250L]LRQRQPREDGNEEDKENQG DETQGQQ YBX2 c.677de|C p.P226fs SAGTGPGSKGERAEDSGQRPRRWCP[p. RWCPHPSST,HPSSTDGGL,CEAPGLPTS,GQRPRRWCPH,R STAD P226fs]HPSSTDGGLCEAPGLPTSSSL* PRRWCPHPS,APGLPTSSSL,RRWCPHPSST,CEAPGLPTSS YIF1A c.391de|C p.R131fs LGLLVFPYTHQNWEVQYSRDAPLPP[p. KTSTPLTSI,SISPRWPSL,LGWHWAFRK,WLGWHWAFR,IS STAD R131fs]GKTSTPLTSISPRWPSLLTCSWL PRWPSLL,SWLGWHWAF,AFRKGSPRR,KGSPRRCWA,TPL GWHWAFRKGSPRRCWACVQAQRWC TSISPR,WAFRKGSPR,CWACVQAQR,PPGKTSTPL,SPRWP GW* SLLT,SPRRCWACV,LLTCSWLGW,RKGSPRRCW,VQAQRW CGW,WPSLLTCSW,WACVQAQRW,SISPRWPSLL,WLGW HWAFRK,STPLTSISPR,SWLGWHWAFR,RWPSLLTCSW,SL LTCSWLGW,CSWLGWHWAF,CWACVQAQRW,TSISPRW PSL,HWAFRKGSPR,WAFRKGSPRR,APLPPGKTST,LPPGKT STPL,SPRWPSLLTC,WPSLLTCSWL,GKTSTPLTSI,TPLTSISP RW YLPM1 c.3533de|A p.E1178fs RGLGRSDFGRDRGPFRPEPGDGGEK[p. LGLHGTMEK,TMEKSEGMK,CIHITGMSLL,IHITGMSLL,SLLG STAD E1178fs]CIHITGMSLLGLHGTMEKSEG LHGTM,EKSEGMKSF,CIHITGMSLL,HITGMSLLGL,GMSLL MKSFH* GLHGT,LLGLHGTMEK,GTMEKSEGMK,MEKSEGMKSF,MS LLGLHGTM,GEKCIHITGM,KCIHITGMSL YTHDC2 c.1900G>A p.E634K IMHLLYNICHSCDAGAVLIFLPGYD[p.E6 FLPGYDKIV,LIFLPGYDK,IFLPGYDKI,VLIFLPGYDK,LPGYDKI CRC 34K]KIVGLRDRILFDDKRFADSTHRYQV VGL F YTHDC2 c.553G>A p.E185K NREMSKTSGRLNNGIPQIPVKRGES[p. RGESKFDSF,IPVKRGESKF,KRGESKFDSF,SKFDSFRQSL UCEC E185K]KFDSFRQSLPVFEKQEEIVKIIKE NK ZAR1 c.126G>C p.Q42H CPPCSYRYPYPAATKGKGAAGGSWQ[p. WQHRGRGCL,WQHRGRGCLP ACC Q42H]HRGRGCLPASSPCSAGAASLSF PGCG ZBBX c.1787G>T p.R596I TKSSLLLQEIACRSKPITKQYQGLE[p.R5 YQGLEIFFI,KQYQGLEIF,QYQGLEIFF,QGLEIFFIF,TKQ CRC 96I]IFFIFDTNERLNLLPSHRLECNNSST YQGLEI,LEIFFIFDT,KQYQGLEIFF,QYQGLEIFFI,YQGL EIFFIF,ITKQYQGLEI,IFFIFDTNER,TKQYQGLEIF ZBBX c.453_455 p.E151 KPKINGKVCGQCENKAALLVCLECG[p.E LVCLECGDY,LLVCLECGDY STAD de|AGA de| 151de|]DYCSGCFAKVHQKGALKLHRT TLLQAKS ZBED4 c.1154C>T p.S385L PSLLPPEGELSSVSSSPVKPVRESP[p.S3 RESPLASSS,RESPLASSSP CESC 85L]LASSSPDRLTEDLQSHLNPGDGLM ED ZBTB2 c.2075de|C p.P692f CKKKFSHKTLLERHVALHSASNGTP[p.P APQAWWPAR,HSASNGTPL,LAPQAWWPA,TPLQAHPQV, STAD 0 s 692fs]LQAHPQVPALAPQAWWPARR WPARRGPLT,WWPARRGPL,LQAHPQVPA,QAHPQVPAL, GPLTSAPSAQQSLTKSSSSTTT* VPALAPQAW,LQAHPQVPAL,ALAPQAWWPA,AWWPAR RGPL,LAPQAWWPAR,APQAWWPARR,WPARRGPLTS,LH SASNGTPL,TSAPSAQQSL,AQQSLTKSSS,VPALAPQAWW ZBTB24 c.1819C>A p.L607I QNMTADQAANLTLLTQQPEQLQNLI[p.L QLQNLIISA,LQNLIISAQ,EQLQNLIISA,QPEQLQNLII CRC 607I]ISAQQEQTEHIQSLNMIESQMG PSQT ZBTB40 c.786_787insA p.L262fs QLNFLLENEGVFSDALMVTQDVLKK[p. VLKKTRNVF,VLKKTRNVFR,VTQDVLKKTR STAD L262fs]TRNVFRN* ZBTB7C c.1025_1026 p.G342fs ELPPPPPPPFPNDFFKDMFPDLPGG[p. VLLQELHAL,HLRGPLHQA,RLRCLSQLP,HVHHLRGPL,QLR STAD insG G342fs]ASGTHQGGERLRCLSQLPECH PQEPHA,HAHPHGRAA,HGRAALPVR,AALPVRVLL,RVLLQ PPGRPLPTLAPGRRAQAEAQGLSAVPH ELHA,AAAAHEDPY,EAIHVHHLR,HPPGRPLPT,RPLPTLAPG, LPQSHHGGREAAAAHEDPYRGEAIHVH HAEAHRGAA,HPLQRQVRA,LQRQVRAQL,RAALPVRVL,SQ HLRGPLHQAGQAENPHAEAHRGAALP LPECHPP,RAQAEAQGL,AEAQGLSAV,AQGLSAVPFI,SHH VHPLQRQVRAQLRPQEPHAHPHGRAA GGREAA,GEAIHVHHL,AENPHAEAH,AEAHRGAAL,AHRG LPVRVLLQELHAL* AALPV,GAALPVHPL,RQVRAQLRP,AQLRPQEPH,FPDLPG GAS,DPYRGEAIH,DMFPDLPGGA,TLAPGRRAQA,AQAEA QGLSA,GQAENPHAEA,AAAAHEDPYR,AALPVHPLQR,RLR CLSQLPE,HVHHLRGPLH,LQRQVRAQLR,HAHPHGRAAL,H GRAALPVRV,RAALPVRVLL,RVLLQE LHAL,HLPQSHHGGR,EAHRGAALPV,HPPGRPLPTL,APG RRAQAEA,HAEAHRGAAL,LPVHPLQRQV,RPQEPHAHPH, HPHGRAALPV,LPVRVLLQEL,EAAAAHEDPY,HQGGERLRCL, GERLRCLSQL,SQLPECHPPG,RRAQAEAQGL,AQGLSAVPHL, HEDPYRGEAI,IHVHHLRGPL,HQAGQAENPH,AHRGAAL PVH,RGAALPVHPL,RQVRAQLRPQ,AQLRPQEPHA, GRAALPVRVL,FPDLPGGASG,AEAQGLSAVP,DPYRGEAIHV ZBTB7 c.460de|G p.D154 ILNAARMLEIQCIVNVCLEIMEPGG[p.D TMMTRRTLL,SLTPSRLAV,CLTPRTSAA,KMMMMRRTK,M STAD C fs 154fs]TGGRRMTRRTMTTTKMMMM MMMRRTKR,MMMRRTKRR,MTRRTLLTK,GTGGRRMTR, RRTKRRRRKRRRMTMMTRRTLLTKKTC TTTKMMMMR,TTKMMMMRR,SAATKALPR,RMTRRTMT LTPRTSAATKALPRQTISQRRPIQTPPGT T,MTRRTMTTT,TRRTMTTTK,RTMTTTKMM,MMRRTKRR SLTPSRLAVLAIWG* R,RTKRRRRKR,RRRMTMMTR,MTMMTRRTL,RTSAATKAL, MTTTKMMMM,QTISQRRPI,RRKRRRMTM,TLLTKKTCL,I QTPPGTSL,RRTMTTTKM,TMTTTKMMM,RKRRRMTMM, TKALPRQTI,SQRRPIQTP,SRLAVLAIW,TMMTRRTLLT,CLT PRTSAAT,SLTPSRLAVL,MTRRTMTTTK,KMMMMRRTKR, MMMMRRTKRR,MMMRRTKRRR,MMTRRTLLTK,MTRRT LLTKK,MTTTKMMMMR,TTTKMMMMRR,LTPRTSAATK,T SAATKALPR,RTMTTTKMMM,MMRRTKRRRR,MRRTKRR RRK,RTKRRRRKRR,RRRKRRRMTM,KRRRMTMMTR,RRR MTMMTRR,RMTMMTRRTL,MTMMTRRTLL,RTLLTKKTCL, LTKKTCLTPR,KTCLTPRTSA,ATKALPRQTI,RQTISQRRPI,TP RTSAATKA,TPSRLAVLAI,RRKRRRMTMM,RMTRRTMTTT, TRRTMTTTKM,RRTMTTTKMM,TMTTTKMMMM,SQRRP IQTPP,IQTPPGTSLT ZBTB7C c.469de|G p.E157fs AARMLEIQCIVNVCLEIMEPGGDGG[p. TMMTRRTLL,SLTPSRLAV,CLTPRTSAA,KMMMMRRTK,M STAD E157fs]RRMTRRTMTTTKMMMMRRT MMMRRTKR,MMMRRTKRR,MTRRTLLTK,TTTKMMMM KRRRRKRRRMTMMTRRTLLTKKTCLTP R,TKMMMMRR,SAATKALPR,RMTRRTMTT,MTRRTMTTT,TR RTSAATKALPRQTISQRRPIQTPPGTSLT RTMTTTK,RTMTTTKMM,MMRRTKRRR,RTKRRRRKR,RRR PSRLAVLAIWG* MTMMTR,MTMMTRRTL,RTSAATKAL,MTTTKMMMM,QTISQRR PI,RRKRRRMTM,TLLTKKTCL,IQTPPGTSL,RRTMTTTKM, TMTTTKMMM,RKRRRMTMM,TKALPRQTI,SQRRPIQTP, SRLAVLAIW,TMMTRRTLLT,CLTPRTSAAT,SLTPSRLAVL, MTRRTMTTTK,KMMMMRRTKR,MMMMRRTKRR, MMMRRTKRRR,MMTRRTLLTK,MTRRTLLTKK,MTTTKMMMM R,TTTKMMMMRR,LTPRTSAATK,SAATKALPR, RTMTTTKMMM,MMRRTKRRRR,MRRTKRRRRK,RTKRRR RKRR,RRRKRRRMTM,KRRRMTMMTR,RRRMTMMTRR,R MTMMTRRTL,MTMMTRRTLL,RTLLTKKTCL,LTKKTCLTPR, KTCLTPRTSA,ATKALPRQTI,RQTISQRRPI,TPRTSAATKA, TPSRLAVLAI,RRKRRRMTMM,RMTRRTMTTT,TRRTMTTTK M,RRTMTTTKMM,TMTTTKMMMM,SQRRPIQTPP,IQTP PGTSLT ZC3H12D c.1213C>T p.P405S SAGGRVPGPLSLPSPESQFSPGDLP[p.P LPSPPGLQL,SQFSPGDLPS ACC 405S]SPPGLQLQPRGEHRPRDLHGDLL SPR ZC3H13 c.3018de|A p.K1006fs NIETTSEDGQVFSPKKGQKKKSIEK[p.K1 LMKKQPSKV,KVILIFLMK,VILIFLMKK,FLMKKQPSK,KNPK STAD 006fs]NVKNPKVILIFLMKKQPSKVRRK VILIF,KQPSKVRRK,KVRRKEAHG,RKEAHGLPL,FLMKKQPS EAHGLPL* KV,KVILIFLMKK,SIEKNVKNPK,IFLMKKQPSK,LMKKQPSKV R,KVRRKEAHGL,RRKEAHGLPL,QPSKVRRKEA,VKNPKVILI F,NPKVILIFLM,IEKNVKNPKV ZC3H18 c.2102_2103 p.T701fs PVPEPTKPGDPREARRKERPARTPP[p.T AKRQRQWQW,RTPPQEADAK,RPARTPPQEA STAD insC 701fs]QEADAKRQRQWQW* ZC3H18 c.2473de|C p.P825fs PKSAKPPAGGKSSQQPSTPQQAPPG[p. RAHLWPTRR,QQAPPGSPS,PSRAHLWPTR,RAHLWPTRRS, STAD P825fs]SPSRAHLWPTRRSS* SPSRAHLWPT ZC3H4 c.2392G>A p.E798K IQQKQQEEEERARRLAESSKQDREN[p. SSKQDRENK,KEGDTGNWY BLCA E798K]KEGDTGNWYSSDEDEGGSSVT SILKT ZC3H7A c.1724G>C p.C575S NGKINLTVFKLLQEHLGEFIFLCEK[p.C5 KSFDHKPRM,FIFLCEKSF,EFIFLCEKSF,KSFDHKPRMI,GEFI TGCT 75S]SFDHKPRMISKRNKDNSTACSHPV FLCEKS TK ZCCHC6 c.2811A>T p.K937N GKHVERALLVELNKISLKEENVCEE[p.K9 NVCEENNSPV KIRC 37N]NNSPVDQSDFFYEFSKLIFTKGKSP T ZCRB1 c.228A>T p.L76F KGVAFILFLDKDSAQNCTRAINNKQ[p.L KQFFGRVIK,RAINNKQFF,INNKQFFGR,NKQFFGRVI,AINNKQ CLL 76F]FFGRVIKASIAIDNGRAAEFIRRRNY FFGR,FFGRVIKASI,RAINNKQFFG,KQFFGRVIKA,CTRAI NNKQF ZCWPW2 c.430G>A p.D144N DRFKGKYVTYDPDGNVEEYHIEFLG[p.D EFLGNPHSR,LGNPHSRSW,IEFLGNPHS,YHIEFLGNPH,FLG CRC 144N]NPHSRSWIKATFVGHYSITLKPEK NPHSRSW CK ZDHHC11 c.750C>G p.H250Q PVQVQTLIVVIIGMLVLLLDFLGLV[p.H2 GLVQLGQLL,VQLGQLLIF,LDFLGLVQL,LLDFLGLVQL, TGCT 50Q]QLGQLLIFHIYLKAKKMTTFEYLIN FLGLVQLGQL,QLGQLLIFHI,GLVQLGQLLI,LVQLGQLLIF N ZDHHC4 c.899G>A p.R300H LFVLYLAATNQTTNEWYRGDWAWCQ[p.R WAWCQHCPL,CQHCPLVAW,WAWCQHCPLV GBM 300H]HCPLVAWPPSAEPQVHRNIH SHGLRS ZDHHC5 c.1947_1949 p.E651de| PTAPYLGRSMSYSSQKAQPGVSETE[p. ETEVALQPL,TEVALQPLL,AQPGVSETEV,ETEVALQPLL,SET STAD de|AGA E651de|]VALQPLLTPKDEVQLKTTYSKS EVALQPL,TEVALQPLLT NGQPKS ZDHHC7 c.948de|C p.P316fs LKSEKPTWERRLRWEGMKSVFGGPP[p. KSVFGGPPH,MKSVFGGPPH STAD P316fs]HSSG* ZEB2 c.3280G>A p.E1094K SYSQHMNHRYSYCKREAEEREAAER[p. KAREKGHLE,KAREKGHLEP CESC E1094K]KAREKGHLEPTELLMNRAYLQ SITPQ ZEB2 c.467G>A p.R156H NNGTVKNANCTSDFEEYFAKRKLEE[p. LEEHDGHAV,EEHDGHAVS,KLEEHDGHAV,EEHDGHAVSI CRC R156H]HDGHAVSIEEYLQRSDTAIIYPE APE ZFAND2B c.446T>C p.I149T IKHRHPLDHDCSGEGHPTSRAGLAA[p.I TSRAGLAAT,RAGLAATSR,ATSRAQAVA,GLAATS KIRC 149T]TSRAQAVASTSTVPSPSQTMPSC RAQA,TSRAQAVAST,LAATSRAQAV TSP ZFC3H1 c.1155de|A p.K385fs KKLGEDEEELSELQLRLLALQSASK[p.K3 QSASKNGNK,LQSASKNGNK STAD 85fs]NGNKKNSR* ZFHX3 c.2287de|G p.E763fs KGNLSIHMQSDKHLNNMQNLQNGGG RQPISVAPA,RSSATLPGR,SSATLPGRR,SVAPAGPPR,ATLP STAD [p.E763fs]SRSSATLPGRRRRRWLRRRR GRRRR,RRRRRWLRR,RRRRQPISV,IMRPTWPGT,TLPGRR QPISVAPAGPPRRPNQKPNPPGGARCV RRR,WLRRRRQPI,RPNQKPNPP,RPTWPGTSA,LQNGGGSRS, IMRPTWPGTSAFT* RRRQPISVA,RCVIMRPTW,PTWPGTSAF,QPISVAPAG, RSSATLPGRR,ISVAPAGPPR,SVAPAGPPRR,RWLRRRRQPI, GSRSSATLPG,ATLPGRRRRR,RRRRRWLRRR,RRRRQPISVA, AGPPRRPNQK,IMRPTWPGTS,LPGRRRRRWL,RPNQKPN PPG,RPTWPGTSAF,WLRRRRQPIS,LRRRRQPISV,LQNGG GSRSS,RRQPISVAPA ZFHX3 c.2330_2332 p.V777de| NNMQNLQNGGGEQVFSHTAGAAAAA[p. HTAGAAAAAA PAAD de|TGG V777de|]AAAAAAANISSSCGAPSPT KPKTKPTWR ZFHX3 c.5677_5678 p.R1893fs LQPSQHPEKKNKLVIKEKEKESQRE[p.R TARCLEGQR,SEGNTARCL,EERVGTRGW,NTARCLEGQR,G STAD,UCEC de|AG 1893fs]GQRRGGRGQHRSEGNTARCL QRRGGRGQH,GQHRSEGNTA,REERVGTRGW,EERVGTRG EGQREERVGTRGWF* WF ZFHX4 c.1224_122 p.L408fs ASTSSSAEQPLGITQMPKAEVNLGG[p. AEVNLGGAV STAD 5insG L408fs]AV* ZFHX4 c.2433G>T p.L811F MTSEKHMHNMMLLQQNMKQIQHNL IQHNLHFGL,NLHFGLAPA,KQIQHNLHF,MKQIQHNLHF,K LUAD H[p.L811F]FGLAPAEAELYQYYLAQNIG QIQHNLHFG,IQHNLHFGLA,LHFGLAPAEA LTGMKL ZFHX4 c.4988C>A p.T1663N IAANVNSPGQGMLDSMSLAAVNSKD[p. NSKDNHLDAK LUAD T1663N]NHLDAKELNKKQTPDLISAQ PAHHPP ZFHX4 c.7533C>A p.H2511Q LPPQLLQYQCDQCTVAFPTLELWQE[p. QQHMHFLAA,ELWQEQQHM,WQEQQHMHF,QEQQHM LUAD H2511Q]QQHMHFLAAQNQFLHSPFLE HFL,LWQEQQHMHF,LELWQEQQHM,WQEQQHMHFL,E RPMDMP QQHMHFLAA,QQHMHFLAAQ,QEQQHMHFLA ZFP14 c.1156C>T p.R386C SIHTGEKPYECKECGKTFRLRQQLV[p.R RLRQQLVCH,QQLVCHQRI,RQQLVCHQRI,LVCHQRIHTR, CRC 386C]CHQRIHTREKPYECMECWKTFSS QQLVCHQRIH YSQ ZFP14 c.50A>T p.Q17L MAHGSVTFRDVAIDFS[p.Q17L]LEEW DFSLEEWEF,RDVAIDFSL,VAIDFSLEEW,IDFSLEEWEF,LEE LUAD EFLDPAQRDLYRDVMWENYSNF WEFLDPA ZFP2 c.449G>T p.R150I TGEKPYKCNVCGKHFIERSSLTVHQ[p.R RSSLTVHQI,SSLTVHQII,RSSLTVHQII CRC 150I]IIHTGEKPYKCNECGKAFSQSMNL TV ZFP3 c.818G>T p.R273I TGEKPYECNECGKTFRVSSQLIQHQ[p.R QIIHTEERY,HQIIHTEER,IQHQIIHTE,HQIIHTEERY CRC 273I]IIHTEERYHECNECGKAFKHSSGLI R ZFP36L2 c.718G>A p.D240N IHNADERRPAPSGGASGDLRAFGTR[p. RAFGTRNAL,GTRNALHLG,NALHLGFPR,TRNALHLGF,RAF LUSC D240N]NALHLGFPREPRPKLHHSLSFS GTRNALH,GTRNALHLGF,RNALHLGFPR,LRAFGTRNAL GFPS ZFP42 c.679G>A p.V227I RAALRKHLLIHGPRDHVCAECGKAF[p. AFIESSKLK,KAFIESSKL,KAFIESSKLK,CGKAFIESSK,AFIESSK GBM V227I]IESSKLKRHFLVHTGEKPFRCTFE LKR,GKAFIESSKL,IESSKLKRHF,AECGKAFIES GC ZFP42 c.791C>T p.T264M HTGEKPFRCTFEGCGKRFSLDFNLR[p.T RMHVRIHTG,DFNLRMHVR,FSLDFNLRM,SLDFNLRMHV, GBM 264M]MHVRIHTGEKRFVCPFQGCNRR RFSLDFNLRM,RMHVRIHTGE,NLRMHVRIHT FIQS ZFP90 c.1772_177 p.R591fs IQHERTHTGEKPYECNECGRAFRKK[p.R AFRKKNQPA,RAFRKKNQPA PRAD 3insA 591fs]NQPA* ZFPM1 c.1330_133 p.E444fs GLAPTPSPGLDRKALAEATNGEARA[p. QLLRAQAPL,RLGDPGQDV,LLRAQAPLL,ALVPGPRSA,RAQ ACC 1de|GA E444fs]ASGPEWRQQRAPGGPQEHQ APLLFR,LLFRPPCAR,RAQAQGAPR,RAALVPGPR,RAWAP GGGGGGAGGGPHPGPRRAWAPGPV GPVA,QGRAVQPHA,GARRAGPGR,RAGPGRGPV,SAVRV ADAVAAQPRPGQGQGRAVQPHAGLQ RARR,AVRVRARRG,RVRARRGAP,RARRGAPRL,RAGAQP PGARRAGPGRGPVPSAVRVRARRGAP AAA,AGRGRGRRR,RGRGRRRRA,RGRRRRADR,RALPRGP RLGDPGQDVRAGAQPAAAGRGRGRR QG,QGRYVLRVR,RVRDHLQQR,CARGRACRA,RGRACRAQ RRADRALPRGPQGRYVLRVRDHLQQR A,RTRRAALVP,SARGGGWGR,RGHARGRRG,RGRRGRPG QQLLRAQAPLLFRPPCARGRACRAQAQ Q,SGPEWRQQR,HAGLQPGAR,LVPGPRSAR,HPGPRRAW GAPRPGPRAPRPARRTRRAALVPGPRS A,GPRRAWAPG,APGPVADAV,RPGQGQGRA,RAVQPHA ARGGGWGRGHARGRRGRPGQRGQP GL,VPSAVRVRA,RRRRADRAL,RPPCARGRA,APRPGPRAP, EPG* RPARRTRRA,ARRTRRAAL,RPGQRGQPE,HLQQRQQLL,AR AASGPEW,RRAWAPGPV,GQGRAVQPH,RQQLLRAQA,LR AQAPLLF,GPVADAVAA,LPRGPQGRY,QLLRAQAPLL,RVR ARRGAPR,RSARGGGWGR,RYVLRVRDHL,AVRVRARRGA, RARRGAPRLG,AGRGRGRRRR,RGRRRRADRA,RRRADRAL PR,RALPRGPQGR,RVRDHLQQRQ,LLRAQAPLLF,LFRPPCA RGR,RGRACRAQAQ,RAPRPARRTR,RTRRAALVPG,RGHA RGRRGR,RGRRGRPGQR,ALPRGPQGRY,HAGLQPGARR,H LQQRQQLLR,WAPGPVADAV,GPHPGPRRAW,RPGQGQG RAV,LPRGPQGRYV,RPPCARGRAC,RPGPRAPRPA,RPARR TRRAA,PARRTRRAAL,GPRSARGGGW,QQLLRAQAPL,RQ QRAPGGPQ,RRAWAPGPVA,GQGRAVQPHA,RRAGPGRG PV,VRARRGAPRL,RDHLQQRQQL,LQQRQQLLRA,RQQLL RAQAP,AQAPLLFRPP,AQAQGAPRPG ZFPM1 c.1335de|T p.P445fs APTPSPGLDRKALAEATNGEARAEP[p. RMEAAASPR,RVAPWTTRR,STCSGPTRR,RALRASSAR,TV ACC P445fs]WPRMEAAASPRRPPGASRWR QAAVRPR,ATSASAATR,CTSGTTAPR,TTAPRATTR,TSCTRP RWRSRRRPPSWAPESLGPRPRRGRRR APR,WAWPGPCSF,RSWPRCPSW,ASRWRRWRS,RWRR RAAPPRPGSRPSCPAPRRAPARCPASW WRSRR,RWRSRRRPP,RSRRRPPSW,RPRRGRRRR,RGRRR AWPGPCSFRSTCSGPTRRPPPRRSWPR RAAP,RRRRAAPPR,RSTCSGPTR,PTRRPPPRR,RARARAPA CPSWCTAGCSRARARAPAARRPGSSPGP A,RARAPAARR,ALRASSARS,RASSARSPS,ASSARSPSA,AV PRALRASSARSPSATSTTTTCTSASTVQ RPRTRLP,RPRTRLPRA,RTRLPRAGP,RLPRAGPRR,RAGPRR AAVRPRTRLPRAGPRRPPARPARPPAS PPA,PARPARPPA,PTRRARPRA,RARPRAPER,RARRGLGAR, PPNPTRRARPRAPERARRGLGARPRPR GARPRPRTA,RPRPRTARA,RTARAAGAA,TARAAGAAR,A TARAAGAARAARARVAPWTTRRTTPA AGAARAAR,AARAARARV,AARARVAPW,RARVAPWTT,TT ARCARPATSASAATRPTPCTSGTTAPRA RRTTPAA,RTTPAARCA,AARCARPAT,ATRPTPCTS,ATTRR TTRRRADRPRPRDPLGRPRPRPPLPPRL RADR,RPRPPLPPR,CTRPAPRPP,RPAPRPPRR,PLRARPAPR, CARADAASSTSCTRPAPRPPRRPATPPR RARPAPRPT,EARAEPWPR,GASRWRRWR,ESLGPRPRR,S PSRRGPEAEAEAAPASPLRARPAPRPTA WCTAGCSR,CTAGCSRAR,QAAVRPRTR,TTPAARCAR,EAA PST* PASPLR,TTCTSASTV,CTSASTVQA,SASTVQAAV,WTTRRT TPA,EPWPRMEAA,WPRMEAAAS,SPRRPPGAS,CPAPRRA PA,APARCPASW,APAARRPGS,RPARPPASP,APERARRGL, RPRTARAAG,RAAGAARAA,APWTTRRTT,RPATSASAA,RP TPCTSGT,RPRPRPPLP,APRPPRRPA,RPATPPRPS,RPSRRG PEA,RPAPRPTAP,APRPTAPST,ARAEPWPRM,RRAPARCP A,ARCPASWAW,AAVRPRTRL,AEAAPASPL,CPASWAWPG, AEAEAAPAS,AEPWPRMEA,LPPRLCARA,STVQAAVRPR,R TARAAGAAR,RTTPAARCAR,GTTAPRATTR,TTAPRATTRR, STSCTRPAPR,SWAWPGPCSF,RMEAAASPRR,AASPRRPP GA,ASRWRRWRSR,RWRRWRSRRR,RWRSRRRPPS,RSRR RPPSWA,RGRRRRAAPP,RAAPPRPGSR,GSRPSCPAPR,SFR STCSGPT,RSTCSGPTRR,SGPTRRPPPR,RSWPRCPSWC,CS RARARAPA,RARARAPAAR,RARAPAARRP,AARRPGSSPG, RALRASSARS,RASSARSPSA,AVRPRTRLPR,RTRLPRAGPR, RAGPRRPPAR,RARPRAPERA,RPRAPERARR,RARRGLGAR P,RGLGARPRPR,GARPRPRTAR,TARAAGAARA,RAAGAAR AAR,AARAARARVA,AARARVAPWT,RARVAPWTTR,TTRR TTPAAR,AARCARPATS,CARPATSASA,ATRPTPCTSG,RATT RRRADR,TTRRRADRPR,RRRADRPRPR,RPRPRDPLGR,RPR DPLGRPR,LGRPRPRPPL,RPRPPLPPRL,CTRPAPRPPR,RAR PAPRPTA,SWAPESLGPR,CPAPRRAPAR,WAWPGPCSFR,R PPPRRSWPR,TAGCSRARAR,SASTVQAAVR,DAASSTSCTR, SPLRARPAPR,CTAGCSRARA,TTTCTSASTV,CTSASTVQAA, TSASTVQAAV,WTTRRTTPAA,CTSGTTAPRA,EAEAAPASP L,EAAPASPLRA,WPRMEAAASP,RPPSWAPESL,RPRRGRR RRA,RPGSRPSCPA,RPSCPAPRRA,APARCPASWA,WPRCP SWCTA,APAARRPGSS,PPRALRASSA,RPRTRLPRAG,LPRA GPRRPP,GPRRPPARPA,RPARPPASPP,RPRPRTARAA,RPR TARAAGA,APWTTRRTTP,TPAARCARPA,RPATSASAAT,R PTPCTSGTT,APRATTRRRA,RPRPRPPLPP,RPPLPPRLCA,A PRPPRRPAT,RPAPRPTAPS,WRSRRRPPSW,RAPARCPAS W,RRSWPRCPSW,ARAAGAARAA,RAARARVAPW,EPWP RMEAAA,AEPWPRMEAA,AEAEAAPASP,PEAEAEAAPA ZFR2 c.319T>A p.Y107N TTMATYQDSYSYGQSAAARSYEDRP[p. RSYEDRPNF,RPNFQSAAL,ARSYEDRPNF,YEDRPNFQSA KIRC Y107N]NFQSAALQSGRMTAADSGQP GTQEAC ZFYVE1 c.797G>A p.R266Q GATVNLSQRTRLLLKVLAISDLVIY[p.R2 IYQTHADRL,VIYQTHADR,YQTHADRLH,AISDLVIYQT,LVIY UCEC 66Q]QTHADRLHNDLFKFLGDASEAYLK QTHADR,VIYQTHADRL HF ZFYVE9 c.3441G>C p.M1147I VVQGLVVDMEVRKTSIKIPSNRYNE[p. SNRYNEIMK,IPSNRYNEI,RYNEIMKAM,IPSNRYNEIM,NRY CESC M1147I]IMKAMNKSNEHVLAGGACFN NEIMKAM EKADSH ZHX3 c.747C>A p.N249K EVREGDHSFINGAVPVSQASASSAK[p. QASASSAKK,ASSAKKPHA,KPHAANGPL,SQASASSAKK,KP STAD N249K]KPHAANGPLIGTVPVLPAGIAQ HAANGPLI,KKPHAANGPL FLSL ZIC1 c.335C>A p.A112E GSYSSAAFNSTRDFLFRNRGFGDAA[p. EAASAQHSL,AEAASAQHS,EAASAQHSLF,RGFGDAAEAA, LUAD A112E]EAASAQHSLFAASAGGFGGPH AEAASAQHSL GHTDA ZIC4 c.914C>T p.S305L GEKPFRCEFEGCERRFANSSDRKKH[p.S HLHVHTSDK,KKHLHVHTS,KHLHVHTSDK,LHVHTSDKPY CRC 305L]LHVHTSDKPYTCKVRGCDKCYTH PSS ZIM3 c.1054G>A p.D352N RIHTGEKPYKCSICEKAFSQKSNVI[p.D3 KSNVINHEK,SQKSNVINH,KSNVINHEKI,INHEKIHTGK CRC 52N]NHEKIHTGKRAYECDLCGNTFIQK KN ZIM3 c.1150de|A p.I384fs GKRAYECDLCGNTFIQKKNLIQHKK[p.I ILGKSPMNV,FIAIRKLIA,KLIAERGPI,SQTFIAIRK,RSQTFIAI STAD 384fs]SILGKSPMNVTDVEKPSFRSQTFI R,TFIAIRKLI,QHKKSILGK,KSILGKSPM,SFRSQTFIA,AIRKLI AIRKLIAERGPIDVVNVEKPSSGN* AER,KPSFRSQTF,NLIQHKKSI,LIQHKKSIL,FRSQTFIAI,AER GPIDVV,SILGKSPMNV,LIAERGPIDV,IQHKKSILGK,RSQTFI AIRK,SFRSQTFIAI,IAIRKLIAER,QTFIAIRKLI,KPSFRSQTFI,N LIQHKKSIL,KKSILGKSPM,SQTFIAIRKL,RKLIAERGPI,NVTD VEKPSF ZKSCAN1 c.1621_162 p.R541fs KCTKCGKAFTRSSTLTLHHRIHARE[p.R5 HRIHARESL,HHRIHARESL UCEC 2de|AG 41fs]SL* ZKSCAN3 c.598_599A p.K200A VGSQPLQDRVLQVPVLAHGGCCRED[p. REDAVVASRL TGCT A>GC K200A]AVVASRLTPESQGLLKVEDVAL TLTPE ZKSCAN4 c.956G>A p.R319Q IPTHAEAGEQEGRLQRKQKNAIGSR[p. NAIGSRQHY,RQHYCHECG,RQHYCHECGK,KNAIGSRQHY CRC R319Q]QHYCHECGKSFAQSSGLTKHR RIHTG ZKSCAN5 c.39de|C p.D13fs MIMTESREVIDLDP[p.D13fs]QLRLPRS* QLRLPRSRK,EVIDLDPQL,RLPRSRKTF,EVIDLDPQLR,DLDP STAD RKTFS QLRLPR,REVIDLDPQL,LRLPRSRKTF ZMIZ1 c.3144de|C p.D1048fs MPEPSLDLLPELTNPDELLSYLDPP[p.D1 IVTMTSCLY,YLDPPTCRA,AIVTMTSCL,TMTSCLYLR,AVGR PRAD 048fs]TCRAIVTMTSCLYLRTTEGHPVG GALPR,SYPTYPTHF,TYPTHFSTW,VTMTSCLYL,AIPPHSAS AIPPHSASYPTYPTHFSTWEPVPSDRPA Y,SYLDPPTCR,SASYPTYPT,RPAPEPRAV,EPRAVGRGA,GA PEPRAVGRGALPRCSPLRTEG* LPRCSPL,RAIVTMTSC,ASYPTYPTH,THFSTWEPV,HPVGAI PPH,YPTYPTHFS,EPVPSDRPA,TEGHPVGAI,YLDPPTCRAI, YLRTTEGHPV,VTMTSCLYLR,LSYLDPPTCR,AIVTMTSCLY,S TWEPVPSDR,RAVGRGALPR,ASYPTYPTHF,PTYPTH FSTW,RAIVTMTSCL,RTTEGHPVGA,RGALPRCSPL,GAL PRCSPLR,GAIPPHSASY,HSASYPTYPT,YPTYPTHFST, RPAPEPRAVG,EPRAVGRGAL,PPHSASYPTY,WEP VPSDRPA ZMIZ2 c.457_501 p.VAAA LGLPSHAARPSTDFTQAAAAAAVAA[p. AAAAAVAAL,AAVAALQEK,AAAVAALQEK,AAAAAAVAAL PAAD de|GT AATAT VAAAAATATATATAT153de|]LQEKQS GGCTG ATATA QELSQYGAMGAGQSFNSQFLQHGGP CTGCGGCA T153de| RGPSVPAGMNPTGIGGVMGPSGLSPL GCCACTGC AMNPTRAAGMTPL CACCGCCA CAGCCACA GCCACC ZMYM4 c.1033de|A p.K345fs SSGMNKMLPSVPATAVRVSCSGCKK[p. LLIRGKGLL,YSAPHCASL,KSSRRGKLL,SSRRGKLLI,RGKLLIR STAD K345fs]SSRRGKLLIRGKGLLSYSAPHCA GK,RGKGLLSYS,AHRLLSPRK,RLLSPRKLV,IRGKGLLSY,CSG SLDIQFHLPAHRLLSPRKLVQVAQKTF* CKKSSR,IQFHLPAHR,PAHRLLSPR,APHCASLDI,LPAHRLLSP,SP RKLVQVA,LVQVAQKTF,GLLSYSAPH,HCASLDIQF,ASL DIQFHL,LDIQFHLPA,FHLPAHRLL,SLDIQFHLPA,IQFHLPAHRL, LLSPRKLVQV,LLSYSAPHCA,SYSAPHCASL,GCKKSSRR GK,KSSRRGKLLI,SSRRGKLLIR,RGKGLLSYSA,PAHRLLSPRK, LIRGKGLLSY,DIQFHLPAHR,LPAHRLLSPR,KLVQV AQKTF,KKSSRRGKLL,LDIQFHLPAH ZMYM4 c.1100C>T p.T367I SGCKKILQKGQTAYQRKGSTQLFCS[p.T CSILCLTGY,QLFCSILCL,ILCLTGYTV,GSTQLFCSI,TQLFCSIL TGCT 367I]ILCLTGYTVPPARPPPPLTKKTCSS CL,QLFCSILCLT,SILCLTGYTV,KGSTQLFCSI,GSTQLFCSIL, C FCSILCLTGY ZMYM4 c.4337G>A p.R1446Q TYLRFFPPLQKQESEPDKLTVGKRK[p.R KQNEDDEVPV CRC 1446Q]QNEDDEVPVGVEMAENTDNP LRCPVR ZNF11 c.554G>T p.R185I TGEKPYKCKECGKAFNQTSHLIRHK[p.R QTSHLIRHKI CRC 7 185I]IIHTEEKPYKCEECGKAFNQSSTLT T ZNF124 c.1015de|A p.T339fs GEKPYECQKCGKAFSRASTLWKHKK[p. KLILEKSPI,ILEKSPINV,KHKKLILEK,KGFNHYSFC,FNHYSFC STAD T339fs]LILEKSPINVKKCKGFNHYSFCQ QK,KKCKGFNHY,LWKHKKLIL,CKGFNHYSF,LILEKSPINV,IL KHEQSHT* EKSPINVK,GFNHYSFCQK,KSPINVKKCK,TLWKHKKLIL,KKL ILEKSPI,VKKCKGFNHY,KCKGFNHYSF ZNF154 c.1223C>A p.T408N RPYECSECGKSFTQNSGLIKHRRVH[p.T HRRVHNGEK,KHRRVHNGEK,RRVHNGEKPY LUAD 408N]NGEKPYECTECGKSFSHNSSLIKH QR ZNF16 c.1354C>T p.R452W HTGEKPYKCSDCGKAFSQSSSLIQH[p.R QSSSLIQHW,QSSSLIQHWR,SQSSSLIQHW CESC 452W]WRIHTGEKPHVCNVCGKAFSYS SVLR ZNF167 c.2048G>T p.R683I TGEKPYECNECGKVFSYSSSLMVHQ[p. LMVHQITHT,SLMVHQITH,SLMVHQITHT,YSSSLMVHQI CRC R683I]ITHTGEKPYKCNDCGKAFSDSSQ LIV ZNF174 c.1057C>A p.P353T CDDCGKSFTWNSELKRHKRVHTGER[p. RVHTGERTY,RVHTGERTYT,KRVHTGERTY TGCT P353T]TYTCGECGNCFGRQSTLKLHQR IHTG ZNF180 c.1202G>T p.R401I TGEKPYECSECGKSFSRSSHLVSHQ[p.R HLVSHQITH,HLVSHQITHT,ITHTGEKPYR, CRC 401I]ITHTGEKPYRCNQCGKSFSQSYVL RSSHLVSHQI VV ZNF180 c.1706G>T p.R569I TGEKPYECSECGKSFNRSSHLVMHQ[p. SHLVMHQII,RSSHLVMHQI,SSHLVMHQII UCEC R569I]IIHTGEKPYECNQCGKSFSQSYVL VV ZNF180 c.1874G>T p.R625I TGEKPYECSQCGKSFRQSSCLTQHQ[p. ITHTGEKPF,TQHQITHTG,QITHTGEKPF UCEC R625I]ITHTGEKPFECNQCGKTFSLSARL IV ZNF19 c.1046G>T p.R349I TGEKPYSCKVCGQAFNFHTKLTRHQ[p. HTKLTRHQI,HQIIHSEEK,TKLTRHQII,IIHSEEKPF,HTKLTRH CRC R349I]IIHSEEKPFDCVDCGKAFSAQEQ QII,RHQIIHSEEK,QIIHSEEKPF LKR ZNF195 c.176G>A p.R59Q LENYRNLFSVGLTVCKPGLITCLEQ[p.R5 QQKEPWNVK,QQKEPWNVKR,LEQQKEPWNV UCEC 9Q]QKEPWNVKRQEAADGHPEMGFH HATQ ZNF205 c.1150C>T p.R384C TGEKPYTCPACRKSFSHHSTLIQHQ[p.R HQCIHTGEK,IQHQCIHTG,CIHTGEKPYV,QCIHTGEKPY CRC 384C]CIHTGEKPYVCDRCAKRFTRRSDL VT ZNF223 c.67G>T p.G23W MTMSKEAVTFKDVAVVFTEEEL[p.G23 FTEEELWLL,EELWLLDLA,EEELWLLDL,VVFTEEELW,WLLD LUAD W]WLLDLAQRKLYRDVMLENFRNLLSV LAQRKL,VFTEEELWLL,ELWLLDLAQR,TEEELWLLDL,EELW G LLDLAQ,EEELWLLDLA ZNF23 c.366de|T p.F122fs NIKKEKSNTIDGTVKDETSPVEECF[p.F1 FLVKVQTHI,KVQTHISVI,SLESSPLGV,IPSLESSPL,VKVQTHI STAD 22fs]LVKVQTHISVIPSLESSPLGVQDW SV,THISVIPSL,VQDWGNPSA,QDWGNPSAL,VEECFLVKV, GNPSALIQNS* SPVEECFLV,VQDWGNPSAL,VIPSLESSPL,CFLVKVQTHI,LV KVQTHISV,QTHISVIPSL,ETSPVEECFL,TSPVEECFLV,VKVQTHISVI ZNF236 c.4229C>T p.T1410M NITLQIDPSILQQTLQQGNLLAQQL[p.T QLMGEPGLA,AQQLMGEPG,QQLMGEPGL,LMGEPGLAP, STAD 1410M]MGEPGLAPQNSSLQTSDSTVP AQQLMGEPGL ASVVI ZNF236 c.4439C>T p.S1480L GPLSEQDSVLTTNSSGTQDLTQVMT[p. TQVMTLQGL,QVMTLQGLV,TQVMTLQGLV,MTLQGLVSP CRC S1480L]LQGLVSPSGGPHEITLTINNSSL S,TQDLTQVMTL SOV ZNF248 c.1703G>T p.R568I TGEKPYECNACGKTFSQRSVLTKHQ[p. HQIIHTRVK,SVLTKHQII,IIHTRVKAL,RSVLTKHQI,LTKHQII CRC R568I]IIHTRVKALSTS* HTR,KHQIIHTRVK,RSVLTKHQII,HQIIHTRVKA ZNF254 c.537G>T p.K179N FQCDKYLKVFYKFLNSNRPKIRHTE[p.K KIRHTENKS,RHTENKSFK,IRHTENKSF,HTENKSFKCK,RPKI UCEC 179N]NKSFKCKKRVKLFCMLSHKTQHK RHTENK,KIRHTENKSF SIY ZNF257 c.1175G>T p.R392I TKEKPYKCEECGKAFNRSSHLTKHK[p.R IIHTREKAY,IIHTREKAYK,KIIHTREKAY,RSSHLTKHKI UCEC 3921]IIHTREKAYKCDEYCKAFN WSSALTT ZNF259 c.521G>T p.R174I LITRAISGLEQDQPARRANKDATAE[p.R IIDEFIVKL,ATAEIIDEF,AEIIDEFIV,ATAEIIDEFI,IIDEFIVKLK, CRC 174I]IIDEFIVKLKELKQVASPFTLIIDDP EIIDEFIVKL,RANKDATAEI ZNF263 c.1529G>T p.R510I TGEKPYKCPECGEIFAHSSNLLRHQ[p.R SNLLRHQII UCEC 510I]IIHTGERPYKCPECGKSFSRSSHLVI ZNF266 c.1031G>A p.R344Q TAKDPFECKICGKSFRNSSCLSDHF[p.R3 HFQIHTGIK,FQIHTGIKP,CLSDHFQIHT,QIHTGIKPYK,FQIH CRC 44Q]QIHTGIKPYKCKDCGKAFTQNSDL TGIKPY TK ZNF266 c.1535G>A p.R512Q TGEKPYKCKQCGKSFSYSNSFQLHE[p.R FQLHEQTHT,EQTHTGEKPY,FQLHEQTHTG CRC 512Q]QTHTGEKPYECKECGKAFSSSSSF RN ZNF268 c.2700_270 p.F901de| NSQLIVHQRTHSGEKPYGCNECGKT[p. KTSQKSILS,KTSQKSILSA BRCA 2de|CTT F901de|]SQKSILSAHQRTHTGEKPCKC TECGKAF ZNF273 c.957T>A p.N319K DCGKVFSVFSVLTKHKIIHTGTKPY[p.N3 IIHTGTKPYK KIRC 19K]KCEECGKGFSIFSTLTKHKIIHTGEK ZNF280B c.1087G>A p.E363K SWENHTTCQHCHRQFPTPFQLQCHI[p. QLQCHIKNV,LQCHIKNVH,CHIKNVHTA,FQLQCHIKNV CRC E363K]KNVHTAQEPSTVCKICELSFETD QVL ZNF280B c.1198G>A p.E400K CKICELSFETDQVLLQHMKDHHKPG[p. HHKPGKMPY,GKMPYVCQV,HMKDHHKPGK,MKDHHKP GBM E400K]KMPYVCQVCHYRSSVFADVET GKM,GKMPYVCQVC HFRTC ZNF283 c.1175G>A p.R392Q KIHTGKKPYECKICGKAFCWGYQLT[p.R GYQLTQHQI,YQLTQHQIF,TQHQIFHTG,GYQLTQHQIF,W CRC 392Q]QHQIFHTGEKPYECKECGKAFNC GYQLTQHQI,YQLTQHQIFH GSS ZNF32 c.185C>T p.S62L EATGSSSWDIQNSFRREKLEQKSPD[p.S KLEQKSPDLK CRC 62L]LKTLQEDSPGVRQRVYECQECGKS FR ZNF322 c.318G>T p.K106N VQSSDLTSHQRIHNYEKPYKCSKCE[p.K ENSFWHHLV,NSFWHHLVL,KCSKCENSF,CENSFWHHL,YK LUAD 106N]NSFWHHLVLSGHQRTHAGKKFY CSKCENSF,CENSFWHHLV TCDI ZNF333 c.1661G>A p.R554Q TGEKLYECATCGQVLSRLSTLKSHM[p.R HMQTHTGEK,KSHMQTHTG,SHMQTHTGEK,MQTHTGEK UCEC 554Q]QTHTGEKPYVCQECGRAFSEPSS PY,QTHTGEKPYV LRK ZNF334 c.1278de|A p.K426fs ECKECGKTFFCQSALTAHQRIHTGE[p.K AVNVENFYV,FVNLPSMCI,FYVRNQPSL,RIHTGENPM,HTG STAD 426fs]NPMNVVNVRKPSFVNLPSMCIE ENPMNV,EVIQERSPM,NAVNVENFY,VVNVRKPSF,VRKPS EVIQERSPMNAVNVENFYVRNQPSLHI FVNL,PSFVNLPSM,QERSPMNAV,MNAVNVENF,VRNQPS R* LHI,LPSMCIEEV,NLPSMCIEEV,VVNVRKPSFV,AVNVENFY VR,SFVNLPSMCI,NVRKPSFVNL,YVRNQPSLHI,MNQVNVE NFY,HTGENPMNVV,NAVNVENFYV,KPSFVNLPSM,NFYV RNQPSL,QRIHTGENPM,GENPMNVVNV,NVVNVRKPSF,E EVIQERSPM,IQERSPMNAV,PMNAVNVENF,LPSMCIEEVI ZNF354B c.1205G>T p.R402I TGEKPFKCSECGRAFSQSASLIQHE[p.R SASLIQHEI,IQHEIIHTG,SLIQHEIIHT,QSASLIQHEI UCEC 402I]IIHTGEKPYRCNECGKGFTSISRLN R ZNF354B c.1825G>A p.D609N GKLFSQRSSLTNHYKIHIEEDSLKA[p.D6 EEDSLKANL,IEEDSLKANL UCEC 09N]NLHV* ZNF358 c.389de|C p.T130fs DPNSDTLSPGDPKVDPISSGLTATP[p.T RIAGEPSAA,SSGLTATPR,ATPRSWPPA,RPGPSPARI,GLTA STAD 130fs]RSWPPAPRCSPPPPARPGPSPA TPRSW,ARIAGEPSA,RIAGEPSAAA,ISSGLTATPR,PARPGP RIAGEPSAAAPG* SPAR,TPRSWPPAPR,APRCSPPPPA,RPGPSPARIA,SGLTAT PRSW,ARIAGEPSAA ZNF382 c.558T>A p.H186Q FGDSTGWEKSLLNTKHEKIHPAVNL[p. NLQKQTERV,LQKQTERVL,KIHPAVNLQK CLL H186Q]QKQTERVLSGKQELIQHQKVQ APEQP ZNF385D c.677C>G p.T226S KRLLYCSLCKVAVNSASQLEAHNSG[p.T SKHKTMLEA,GSKHKTMLEA,SQLEAHNSGS,LEAHNSGSKH LUAD 226S]SKHKTMLEARNGSGTIKAFPRAG VKG ZNF43 c.752de|A p.N251fs GEKPYTCEECGKVFNWSSRLTTHKK[p. ILDTNSTNV,KLLTSPQSL,LLTSPQSLL,IILDTNSTNV,KLLTSP STAD N251fs]IILDTNSTNVKNVAKLLTSPQSL QSLL,ILDTNSTNVK,SSRLTTHKKI,DTNSTNVKNV,LTSPQSL LPIR* LPI,RLTTHKKIIL,AKLLTSPQSL ZNF43 c.838C>T p.R280C YKLYKCEECGKAFNKSSILTTHKII[p.R28 IICTGEKFY,KIICTGEKF,IICTGEKFYK,CTGEKFYKCK,THKIICT UCEC 0C]CTGEKFYKCKECAKAFNQSSNLTEH GEK,KIICTGEKFY,HKIICTGEKF K ZNF434 c.916C>T p.R306C QNSQIYRAMAEGLWEQGFLRTPEQC[p. RTPEQCCTK,CTKFKSLQL,TPEQCCTKF,RTPEQCCTKF CRC R306C]CTKFKSLQLSYRKVRRGRVPEP CIFY ZNF439 c.785G>T p.R262I TGEKPYECKQCGKSFSYSATHRIHE[p.R ITHIGEKPY,HRIHEITHI,YSATHRIHEI CRC 262I]ITHIGEKPYECQECGKAFHSPRSC HR ZNF442 c.926G>A p.R309Q ERTHTGEKPYKCKRCGRAFSVSSSL[p.R SSSLQIHER,FSVSSSLQI,VSSSLQIHER,RAFSVSSSLQ, UCEC 309Q]QIHERTHTGEKPYECKQCGKAFH FSVSSSLQIH HLG ZNF443 c.902G>T p.R301I TGEKPYKCKQCSKAFPDSSSCLIHE[p.R3 CLIHEITHT,SSSCLIHEI,DSSSCLIHEI,EITHTGEKPY CRC 01I]ITHTGEKPYTCKQCGKAFSVSGSLQ R ZNF445 c.2044C>A p.L682M ECREGFRQSPDCSQPQGAPAVEKTF[p. TFMCQQCGK,KTFMCQQCG,APAVEKTFM,MCQQCGKTF, CRC L682M]MCQQCGKTFTRKKTLVDHQRI KTFMCQQCGK,FMCQQCGKTF HTGEK ZNF454 c.1127G>T p.R376I TGEKPFECNECGKAFRVNSSLTEHQ[p. SSLTEHQII,TEHQIIHTG,SLTEHQIIHT UCEC R376I]IIHTGEKPYKCNECGKAFRDNSS FAR ZNF454 c.569G>T p.S190I SDQSQGFQPSKNAFECSECGKVFSK[p. KVFSKISTL,FSKISTINK,ISTLNKHQK,VFSKISTLNK,KISTLNK LUAD S190I]ISTLNKHQKIHNEKNANQKIHIKE HQK,GKVFSKISTL,SECGKVFSKI KR ZNF462 c.1948T>A p.S650T FCDNLPKFEGQPSSLPLENETDSHP[p.S PTSSNTVKK,DSHPTSSNTV,LENETDSHPT KIRC 650T]TSSNTVKKSQTSILGLSSKNNFVA KA ZNF470 c.1922G>T p.R641I TGEKPYECNVCGKAFSHRKSLTLHQ[p.R KSLTLHQII,RKSLTLHQI,KSLTLHQIIH,RKSLTLHQII CRC 641I]IIHTGEKPYECKECSKAFSQVAH LTL ZNF471 c.845G>T p.R282I TGEKLFECKECRKAFKQSEHLIQHQ[p.R SEHLIQHQI,SEHLIQHQII CRC 282I]IIHTGEKPYKCKECRKAFRQPAHL AQ ZNF48 c.704G>A p.R235H HQRTHTGEKPYKCGICGKGFGDSSA[p. SSAHIKHQR,HIKHQRTHR,KGFGDSSAH,AHIKHQRTH,DSS LUSC R235H]HIKHARTHRGEQPPRPVVPRR AHIKHQR,KGFGDSSAHI QPSRA ZNF48 c.739de|C p.P247fs ICGKGFGDSSARIKHQRTHRGEQPP[p. RTSHISALI,HISALIAAR,RPRTSHISA,AARGLCSAA,LPRDRR STAD P247fs]DQWCPDGSHLGQPRQLPRDR PRT,SHISALIAA,LIAARGLCSA,RQLPRDRRPR,RTSHISALIA, RPRTSHISALIAARGLCSAAAS* TSHISALIA,AARGLCSAAA,HLGQPRQLPR,SHISALIAAR,L PRDRRPRTS,RPRTSHISAL,DQWCPDGSHL,IAARGLCSAA ZNF484 c.412C>T p.R138C SILEELWKDDEHTRKCGENQNKPLS[p. NQNKPLSCV,LSCVVFINK,NKPLSCVVF,KPLSCVVFI,NQNK CRC R138C]CVVFINKKTLANDSIFEYKDIGEI PLSCVV,PLSCVVFINK,LSCVVFINKK,QNKPLSCVVF VH ZNF485 c.1121G>T p.R374I SGNKPYQCRDCGKAFTKSSTLTGHQ[p. KSSTLTGHQI UCEC R374I]IIHTGEKPYHCKKCGKAFRHSSGL VE ZNF488 c.617G>A p.R206Q PAGESADALGELSGLLNTTDLACWG[p. QLSTPKLLV,GQLSTPKLL,CWGQLSTPKL, UCEC R206Q]QLSTPKLLVGDLWNLQALP GQLSTPKLLV QNAPLCS ZNF491 c.1028G>A p.R343Q ERTHTGEKPDGCKQCGKAFRSAKYI[p.R SAKYIQIHG,RSAKYIQIH,FRSAKYIQI,IQIHGRTHT,AFRSAK CRC 343Q]QIHGRTHTGEKPYECKQCGKAF YIQI,SAKYIQIHGR,IQIHGRTHTG HCVS ZNF492 c.1175C>A p.P392H CEVCSKAFSRFSHLTTHKRIHTGEK[p.P3 RIHTGEKHY,RIHTGEKHYK,KRIHTGEKHY LUAD 92H]HYKCEECGKAFNLSSQLTTHKIIHT G ZNF514 c.242T>G p.V81G PGEEGTTNSFLKARPRDLMTFEDVA[p. MTFEDVAGE,MTFEDVAGEF,VAGEFSQWEW KIRP V81G]GEFSQWEWGQLNPAQKDLYRE VMLEN ZNF519 c.1291C>T p.H431Y CKECGKAFNRASHLTQHQRIHTGEK[p. YFKCKECGK,QRIHTGEKY,RIHTGEKYF, KIRC H431Y]YFKCKECGKAFNRGSHLTRHQR RIHTGEKYFK,HTGEKYFKCK,KYFKCKE IHTG CGK,HQRIHTGEKY,QRIHTGEKYF ZNF521 c.1918G>T p.G640C TSLKMMQAVGGAPARPTGEYICNQC[p. ICNQCCAKY,GEYICNQCC,YICNQCCAKY,CAKYTSL LUAD G640C]CAKYTSLDSFQTHLKTHLDTV DSF,NQCCAKYTSL,GEYICNQCCA LPKLT ZNF521 c.809C>A p.P270H TQKCSQCEEGFDFPEDLQKHIAECH[p.P LQKHIAECHH LUAD 270H]HECSPNEDRAALQCVYCH ELFVEETS ZNF528 c.836G>A p.R279Q SNLSQHQRIHTGEKPYKCHECDKVF[p. KVFQSSSKL,FQSSSKLAQ,KVFQSSSKLA, CRC R279Q]QSSSKLAQHQRIHTGEKPYKCH FQSSSKLAQH,HECDKVFQSS ECDK ZNF534 c.1749T>A p.N583K TGEKPYSCNECGKVFSRNSHLARHR[p. RKIHTGEKPH GBM N583K]KIHTGEKPHSCNECGKVFSRNS HLAR ZNF536 c.1987G>T p.G663W RVFRTYHQVVVHSRVHKRDRKGEED[p. EEDWLHVGL,DWLHVGLDER,GEEDWLHVGL LUAD G663W]WLHVGLDERRGSGSDQESQS VSRSTT ZNF536 c.556G>T p.G186C PYCDHRAAQKGNLKIHLRTHKLGNL[p. RTHKLGNLC,RTHKLGNLCK,NLCKGRGRVR LUAD G186C]CKGRGRVREENRLLHELEERAIL RDK ZNF559 c.850G>A p.E284K PSSSHLRECVRIYGGERPYTHKEYV[p.E2 KTFSHSTAL,THKEYVKTF,KEYVKTFSH,VKTFSHSTA,Y UCEC 84K]KTFSHSTALFVHMQTQDGEKFYEC VKTFSHSTA,KTFSHSTALF,YTHKEYVKTF,RPYTHKE KA YVK,VKTFSHSTAL,KEYVKTFSHS ZNF563 c.622de|T p.W208fs NLRRHMVVQGGNRPYKCKLCGKAFF[p. AFFGPVYYV,VLKPFLFTV,KAFFGPVYY,CMKELTLER,FFGPV GBM W208fs]GPVYYVCMKELTLERNRMNV YYVC,VYYVCMKEL,SSVLKPFLF,CGKAFFGPV,GKAFFGPVY, SSVLKPFLFTVPIEDMRECTLGRNRMN FTVPIEDMR,KPFLFTVPI,NVSSVLKPF,KAFFGPVYYV,SVLK VSSVLKPCLIPVPI* PFLFTV,FLFTVPIEDM,FFGPVYYVCM,YYVCMKELTL,VSSV LKPFLF,CGKAFFGPVY,GKAFFGPVYY,NVSSVLKPFL,MNVS SVLKPF,KELTLERNRM,LKPFLFTVPI ZNF563 c.78G>T p.K26N MDAVAFEDVAVNFTQEEWALLGPSCTI[p.K PSQNNLYRY,LLGPSQNNL,SQNNLYRYV,LGPSQNN CRC 26N]NNLYRYVMQETIRNLDCIRMI LY,QNNLYRYVM,ALLGPSQNNL,LLGPSQNNLY,SQNN WEEQN LYRYVM,GPSQNNLYRY ZNF573 c.1049G>T p.R350I TGKKPYECKECGKGYTTASYFLLHQ[p.R FLLHQIIHK,SYFLLHQII,HQIIHKGGK,IIHKGGKPY,ASYFLLH CRC 350I]IIHKGGKPYECKECKKTFTLYRNLT QI,QIIHKGGKPY,TASYFLLHQI,ASYFLLHQII R ZNF578 c.931G>A p.G311S PYKCNECGKSFSYKSSLTCHRRCHT[p.G CHRRCHTSEK CLL 311S]SEKPYKCNECGKSFSYKSSLTCH HRC ZNF583 c.1031G>T p.R344I TGERPFECIECGKAFSNGSFLAQHQ[p.R SFLAQHQII,GSFLAQHQI,FLAQHQIIH,FLAQHQIIHT,GSFL CRC 344I]IIHTGEKPYVCNVCGKAFSHRGYLI AQHQII V ZNF585A c.1473G>T p.E491D YMCNKCGKAFTNRSNLITHQKTHTG[p. HQKTHTGDK,KTHTGDKSY,KTHTGDKSYI,QKTHTGDKSY CRC E491D]DKSYICSKCGKAFTQRSDLITHQ RIH ZNF585A c.1912G>A p.E638K KSFTSKSQLLVHQPVHTGEKPYVCA[p.E VCAKCGKAF,KPYVCAKCGK,YVCAKCGKAF,G CRC 638K]KCGKAFSGRSNLSKHQKTHTGEK EKPYVCAKC PYI ZNF592 c.1498C>A p.P500T PGSQTGKKQQSTALQASTLAPANLL[p. LLTKAVHLA,NLLTKAVHL,TKAVHLANL,NLLTKAVHLA,TLA TGCT P500T]TKAVHLANLNLVPHSVAASVTA PANLLTK,LTKAVHLANL,APANLLTKAV KSSV ZNF592 c.970A>C p.K324Q VTKEDQPGHTKDLSGPTKESSKGSP[p.K SSKGSPQMPK,QMPKSPKSPR,KESSKGSPQM TGCT 324Q]QMPKSPKSPRSPLEATRKSIKPSD SP ZNF594 c.860G>T p.R287I TGEKPYECYDCGQMFSQSSHLVPHQ[p. HLVPHQIIH,IIHTGEKPLK,SSHLVPHQII UCEC R287I]IIHTGEKPLKCNECEKAFRQHSH LTE ZNF598 c.74A>G p.E25G MAAAGGAEGRRADMEAEAAAAPER[p. AEAAAAPERG ACC,KIRP E25G]GGGSCVLCCGDLEATALGRCDH PVCY ZNF608 c.1393de|G p.A465fs SAAAAPGSEASFTESRGLQNKNRGG[p. QIVLLRISK,KNRGGPMGK,LLRISKPAL,KPALPPPTK,GPMG STAD A465fs]PMGKGGGAASMPADEGHPQI KGGGA,PPTKGKTSL,GKGGGAASM,TKGKTSLQW,GKTSL VLLRISKPALPPPTKGKTSLQWSWT* QWSW,DEGHPQIVL,MPADEGHPQ,HPQIVLLRI,VLLRISKP AL,ISKPALPPPT,EGHPQIVLLR,MPADEGHPQI,GPMG KGGGAA,MGKGGGAASM,LQNKNRGGPM,KGKTS LQWSW,DEGHPQIVLL ZNF611 c.1169G>T p.R390I TGEKPYKCEECDKVFSRKSTIETHK[p.R3 RKSTIETHKI UCEC 90I]IIHTGEKPYRCKVCDTAFTWHSQLA R ZNF625 c.704G>A p.R235Q TGEKPYECSECGKAFHSSTCLHAHK[p.R STCLHAHKK,SSTCLHAHKK,AHKKTHTGEK CRC 235Q]KTHTGEKPYECKQCGKAFVSFNS VRY ZNF626 c.1418A>G p.K473R TGEKFYKCEECGKAFKCSSNLTTHK[p.K CSSNLTTHKR LUSC 473R]RIHTGERPYKCEECGKAFNQSSIL TT ZNF638 c.1198G>A p.D400N SQADIPIRSPFGIVKASWLPKFSHA[p.D KFSHANAQK,HANAQKMKR,FSHANAQKM,WLPKFSHAN LIHC 400N]NAQKMKRLPTPSMMNDYYAAS A,FSHANAQKMK,KFSHANAQKM PRIFP ZNF644 c.61G>T p.G21W MRSFLQQDVNKTKSRLNVLN[p.G21 RLNVLNWLA,WLANNMDDL,VLNWLANNM,KSRLNVLN LUAD W]WLANNMDDLKINTDITGAKEELLDD W,SRLNVLNWL,WLANNMDDLK,KSRLNVLNWL,NVLNWL N ANNM,TKSRLNVLNW ZNF645 c.460C>T p.R154C SLQAHIKRRHKRARKQVTSASLEKV[p.R SLEKVCPHI,LEKVCPHIA UCEC 154C]CPHIAPPQTEISDIPKRLQDRDHL SY ZNF649 c.593G>T p.R198I NIEKAHECTDCGKAFLKKSQLTEHK[p.R SQLTEHKII,IIHTGKKPHV,KKSQLTEHKI,SQLTEHKIIH UCEC 198I]IIHTGKKPHVCSLCGKAFYKKYRLT E ZNF652 c.981G>T p.K327N VSCNKSFKKLWSLHEHIKIVHGYAE[p.K IVHGYAENK,AENKFSCEI,KIVHGYAENK,IVHGYAENKF, CRC 327N]NKFSCEICEKKFYTMAHVRKHM AENKFSCEIC VAHT ZNF674 c.1214G>T p.R405I TKENIYECSKCGKSFRGKSHLSVHQ[p.R SHLSVHQII,KSHLSVHQI,KSHLSVHQII,GKSHLSVHQI UCEC 405I]IIHTGEKPYECSICGKTFSGKSHLSV ZNF675 c.659G>T p.R220I TKVNFCKCEECEKAVNQSSKLTKHK[p.R KLTKHKIIY,IIYTCEKLY,SSKLTKHKI,IIYTCEKLYK,SSKL UCEC 220I]IIYTCEKLYKCQECDRTFNQFSNLT TKHKII,KHKIIYTCEK,KIIYTCEKLY,SKLTKHKIIY, E HKIIYTCEKL ZNF676 c.127C>A p.P43T PDLIIFLEQGKEPWNMKRHEMVEEP[p. HEMVEEPTV,EPTVICSHF,HEMVEEPTVI,EEPTVICSHF LUSC P43T]TVICSHFSQEFWPEQGIEDSFQK MIL ZNF677 c.1352G>T p.R451I PGEKPHKCNVCGRAFIQSSSLVEHQ[p. SSLVEHQII,VEHQIIHTG,SLVEHQIIHT CRC R451I]IIHTGEKPYKCNKCDKAFIKRSHL WG ZNF677 c.392G>C p.R131T FDSLWDYDVKNYKGMPLTCNKNLTH[p. HTKDQQHNK,CNKNLTHTK CESC R131T]TKDQQHNKSSIHFSLKQSVSIR DSAH ZNF680 c.1501C>T p.R501W TLANHKRIHAREKPYKCEECGKAFN[p.R FNWSSHLTR,WSSHLTRHKK,AFNWSSHLTR,FNWSSHLTR TGCT 501W]WSSHLTRHKKIHTGEKLYKPEKC H DNN ZNF687 c.2573T>G p.F858C DTVFTHKPLLSSHFDQHLLPQRVSV[p.F LLPQRVSVC,CKCPSCPLLF KIRC 858C]CKCPSCPLLFAQKRTMLEHLKNT HQS ZNF699 c.122G>T p.R41I QDSVVFEDVAVDFTQEEWALLDLAQ[p. LLDLAQINL,DLAQINLYR,LDLAQLNLY,AQINLYRDV,QINLY CRC R41I]INLYRDVMLENFQNLASLGYPLH RDVM,WALLDLAQI,LLDLAQINLY,ALLDLAQINL,AQIN TPH LYRDVM ZNF7 c.1010G>T p.R337I TGEKPYRCEECGKAFGQSSSLIHHQ[p.R SSSKLIHHQI,SSLIHHQII,SLIHHQIIHT,QSSSLIHHQI CRC 337I]IIHTGERPYGCRECGKAFSQQSQL VR ZNF70 c.731G>T p.R244I TGKRPYECRECGKDFSRSSSLRKHE[p.R SLRKHEIIH,RSSSLRKHEI,EIIHTGERPY CRC 244I]IIHTGERPYQCKECGKSFNQSSGLS Q ZNF700 c.1946C>G p.S649C NLRKHGRTHTGEKPYECKQCGKAFR[p. KAFRCASNL,FRCASNLQM,CASNLQMHER,AFRCASNLQM, CLL S649C]CASNLQMHERTHTGEKPYECKE GKAFRCASNL CEKA ZNF700 c.1954A>C p.N652H KHGRTHTGEKPYECKQCGKAFRSAS[p. ASHLQMHER,AFRSASHLQ,RSASHLQMH,FRSASHLQM,S CLL N652H]HLQMHERTHTGEKPYECKECE ASHLQMHER,AFRSASHLQM KAFCK ZNF700 c.1961A>G p.Q654R GRTHTGEKPYECKQCGKAFRSASNL[p. ASNLRMHER,AFRSASNLR,FRSASNLRM,KAFRSASNLR,SA CLL Q654R]RMHERTHTGEKPYECKECEKAF SNLRMHER,AFRSASNLRM CKFS ZNF705A c.892G>A p.D298N GNKIIHTGEKPHACLLCGKAFSLSS[p.D2 AFSLSSNLR,KAFSLSSNLR CLL 98N]NLR* ZNF706 c.23T>A p.I8N MARGQQK[p.I8N]NQSQQKNAKKQA QQKNQSQQK,KNQSQQKNAK BLCA GQKKKQGHDQKAAA ZNF709 c.1403G>T p.R468I TGEKPYECKQCGKAFSCSSSFRMHE[p. RMHEIIHTG,SFRMHEIIH,SSFRMHEII,SFRMHEIIHT,CSSSF UCEC R468I]IIHTGEKPYECKQCGKAFSFSSSF RMHEI,SSFRMHEIIH RM ZNF71 c.1231G>T p.V411L ICKKHFTGRSSLIVHQIVHTGEKPY[p.V4 YLCGECGKA,LCGECGKAF,YLCGECGKAF,GEKPYLCGEC LUAD 11L]LCGECGKAFSQSAYLIEHQRIHTGE K ZNF711 c.2211de|A p.L737fs SVHTKDQPLKCKRCKRGFRQQNELK[p. RQQNELKNI STAD L737fs]NI* ZNF716 c.788A>T p.H263L EKPYRCEECGKAFSWSASLTKHKRI[p.H LTKHKRILT,SLTKHKRIL,KHKRILTGEK LUAD 263L]LTGEKPYTCEERGKVFSRSTLTNY KR ZNF717 c.1781A>T p.N594I GKSFHCKSFLTIHQRTHAGKKPYEC[p.N YECIECEKTF MM 594I]IECEKTFINKLNLGIHKRTHTGERP Y ZNF717 c.2530T>A p.C844S CRKTFSQKSKLFVHHRTHTGEKPFR[p.C RSNECRKTF,KPFRSNECRK,RSNECRKTFS,FRSNECRKTF MM 844S]SNECRKTFSQKSGLSIHQRTHTGE KP ZNF717 c.945G>C p.W315C KPSISKSDLMLQCKMPTEEKPYACN[p. KPYACNCCEK,YACNCCEKLF MM W315C]CCEKLFSYKSSLIIHQRIHTGEKP YG ZNF750 c.287_288 p.S96fs LDPKQTNQPDATAKPASSKSVANGL[p. RVFPHQVGL,GLPHSWLPL,RLTFPSTRV,SVANGLCLR,SAFC HNSC de|CT S96fs]CLRLEASAQLCQGRHQGKPGAA ICSSR,HSWLPLESR,SWLPLESRL,GSRPRCPAC,SGRRSSAFC, SPGNPQVPGTEASPPQGITLQEPSSGSR GARQRRGAR,AFCICSSRR,QTQGARQRR,FTQPHCQGR,R PRCPACSGRRSSAFCICSSRRAQTQGAR PRCPACSG,QPHCQGRVF,FPHQVGLPH,LPLESRLTF,CSGR QRRGARDTGFTQPHCQGRVFPHQVGL RSSAF,KSVANGLCL,LRLEASAQL,HQGKPGAAS,RRGARDT PHSWLPLESRLTFPSTRVST* GF,HQVGLPHSW,TEASPPQGI,LESRLTFPS,SVANGLCLRL, GLCLRLEASA,CLRLEASAQL,FTQPHCQGRV,KSVANGLCLR, SSAFCICSSR,SAFCICSSRR,WLPLESRLTF,SSGSRPRCPA,GS RPRCPACS,RPRCPACSGR,SGRRSSAFCI,SSRRAQTQGA,R AQTQGARQR,RVFPHQVGLP,EASAQLCQGR,TLQEPSSGS R,ESRLTFPSTR,EASPPQGITL,SKSVANGLCL,HQGKPGAAS P,ACSGRRSSAF,RQRRGARDTG,QRRGARDTGF,TQPHCQ GRVF,GRVFPHQVGL,HQVGLPHSWL,VGLPHSWLPL,HSW LPLESRL,LESRLTFPST ZNF765 c.761C>T p.S254L LLRKHQLIHLGEKQYKCDICGKVFN[p.S KVFNLKRYV,FNLKRYVAR,GKVFNLKRY,KVFNLKRYVA,CG UCEC 254L]LKRYVARHRRCHTGEKPYKCNEC KVFNLKRY,DICGKVFNLK,VFNLKRYVAR,NLKRYVARHR GKT ZNF774 c.1268G>A p.R423Q TGERPYKCGECGKSFNQSSHFITHQ[p.R FITHQQIHL,QIHLGDRPY,SHFITHQQI,SSHFITHQQI,QQIH CRC 423Q]QIHLGDRPYRCPECGKTFNQRSH LGDRPY,QIHLGDRPYR,SHFITHQQIH FLT ZNF780A c.1397G>A p.R466Q SNEKPFVCRECEMAFRYHCQLIEHS[p.R HSQIHTGDK,QIHTGDKPF,CQLIEHSQI,QLIEHSQIH,QLIEH UCEC 466Q]QIHTGDKPFECQDCGKAFNRGS SQIHT,SQIHTGDKPF,CQLIEHSQIH SLVQ ZNF782 c.1450G>T p.G484W FNYKSILIVHQRTHTGEKPFECNEC[p.G NECWKSFSH,KPFECNECW,CWKSFSHMSG,FECNECWKSF, LUAD 484W]WKSFSHMSGLRNHRRTHTGER NECWKSFSHM,WKSFSHMSGL PYKCD ZNF782 c.434G>T p.C145F KPHNRDINIFRARMMPCKCDIAGSA[p. SAFQGLSLM,KCDIAGSAF,IAGSAFQGL,GSAFQGLSL,FQG TGCT C145F]FQGLSLMAPHCQYSKEKAHER LSLMAP,DIAGSAFQGL,CKCDIAGSAF,AGSAFQGLSL,GSAF NVCDK QGLSLM,SAFQGLSLMA,FQGLSLMAPH ZNF782 c.740A>C p.K247T KAFLEKAALVTSNSTHPKGKSYNFN[p.K KGKSYNFNT,KSYNFNTFG,GKSYNFNTF,FNTFGENKY,NTF CRC 247T]TFGENKYDKSTFIIPQNMNPEKS GENKYDK,KGKSYNFNTF HYE ZNF799 c.121T>G p.W41G IRVDAGHKPHEYQEYGEKRNTRKQF[p. KQFGKTFSY,RNTRKQFGK,TRKQFGKTF,KRNTRKQFGK,RK BLCA W41G]GKTFSYCHSFQTHKISHTGHKPY QFGKTFSY,KQFGKTFSYC,GKTFSYCHSF DCK ZNF799 c.127A>G p.T43A VDAGHKPHEYQEYGEKRNTRKQFWK[p.T KQFWKAFSY,KAFSYCHSF,NTRKQFWKA,TRKQFWKAF,KA BLCA 43A]AFSYCHSFQTHKISHTGHKPYD FSYCHSFQ,RKQFWKAFSY,NTRKQFWKAF,WKAFSYCHSF, CKEC KQFWKAFSYC ZNF799 c.1357T>C p.C453R KAYRISSSLRRHETTHTGEKPYKCK[p.C4 KPYKCKRGK,KCKRGKAFI,RGKAFIDFY,YKCKRGKAF,KRGK TGCT 53R]RGKAFIDFYSFQNHKTTHAGEKPY AFIDF,RGKAFIDFYS,KRGKAFIDFY,KPYKCKRGKA,CKRGKA EC FIDF ZNF804B c.1930_1931 p.P644S NDIDEDLSFPSYISRFKKHKLIPCS[p.P64 KLIPCSSHL,IPCSSHLEF,HKLIPCSSH,LIPCSSHLEF,HKLIPCSS TGCT CC>AG 4S]SHLEFEDERQFNCKSSPCTVGGHSD HL HG ZNF814 c.959_960 p.G320E KHECGECGKSFSKYVSFSNHQRVHT[p. HQRVHTEKR,RVHTEKRPY,RVHTEKRPYE,QRVHTEKRPY KIRP GG>AA G320E]EKRPYECGECGKSFSKYASFSNH QRVH ZNF814 c.968C>A p.P323H CGECGKSFSKYVSFSNHQRVHTGKR[p. RVHTGKRHY,RVHTGKRHYE,HQRVHTGKRH,QRVHTGKR KIRP P323H]HYECGECGKSFSKYASFSNHQR HY VHTE ZNF814 c.970T>C p.Y324H GECGKSFSKYVSFSNHQRVHTGKRP[p. RVHTGKRPH,RVHTGKRPHE TGCT Y324H]HECGECGKSFSKYASFSNHQRV HTEK ZNF823 c.1640G>T p.R547I SGEKPYECKECGKAFSWLTCLLRHE[p.R WLTCLLRHEI UCEC 547I]IIHTGEKPYECLQCGKAFTRSRFLR G ZNF831 c.146_147 p.A49fs PGGQASPHLTLGPVLLPPEQGLAPP[p. ALHTQPCAA,HGASRGPPA,ASRGPPAPR,RALHTQPCA,DG STAD insC A49fs]HCVPEGPAHPTVPHGASRGPPA QPRWGQR,QPRWGQRAL,ALHTQPCAAA,RALHTQPCAA, PRPASDGQPRWGQRALHTQPCAAA* VPEGPAHPTV,GQPRWGQRAL,GQRALHTQPC,RPASDGQ PRW ZNF831 c.1849C>A p.Q617K AREAMAGKGRAGGRKCGQRRLKMFS[p. RLKMFSKEK,MFSKEKWQV,QRRLKMFSK,FSKEKWQVY,LK LUAD Q617K]KEKWQVYGDETFKRIYQKM MFSKEKW,KMFSKEKWQV,GQRRLKMFSK,RRLKMFSKEK, KASPHGG MFSKEKWQVY,RLKMFSKEKW ZNF831 c.2847G>T p.E949D QAPRVLSALADNAFSPKYLLRLPQA[p.E RLPQADTPL,PQADTPLPL,LPQADTPLPL,LRLPQADTPL CRC 949D]DTPLPLPIPWGPRHSQDSLCSSG WPE ZNF831 c.4178G>A p.R1393Q EGDCRQTLGTLSLGTSSRIVREMDK[p.R REMDKQTVK,QTVKDISPSA SKCM 1393Q]QTVKDISPSAGEHGDCTTHSTA ATSG ZNF836 c.1712T>A p.I571N RIHTGEQPYKCNVCGKVFNYSGNLS[p. YSGNLSNHK,FNYSGNLSNH CLL I571N]NHKRIHTGEKPFQCNECGTVFR NYSC ZNF836 c.1822A>C p.K608Q QCNECGTVFRNYSCLARHLRIHTGQ[p. RIHTGQQPY,GQQPYKCNV,RIHTGQQPYK,LRIHTGQQPY CLL K608Q]QPYKCNVCGKVFNDSGNLSNH KRIHT ZNF836 c.1889G>T p.R630I TGQKPYKCNVCGKVFNDSGNLSNHK[p. KIIHTGEKPF UCEC R630I]IIHTGEKPFQCNECGKVFSYYSC LAR ZNF836 c.2561G>T p.R854I TGDKPYKCNECGKAFIERSKLVYHQ[p.R KLVYHQINH,HQINHTGEK,RSKLVYHQI,INHTGEKPY,KLVY UCEC 854I]INHTGEKPYKCIECGKAFGRFSCLN HQINHT,RSKLVYHQIN,INHTGEKPYK,QINHTGEKPY K ZNF841 c.2270G>T p.R757I TGEMPYKCIECGKVFNSTTTLARHR[p.R TTTLARHRI UCEC 757I]IIHTGEKPYKCNECGKVFRYRSGLA R ZNF845 c.1269G>A p.M423I LTRHRRLHTGEKPYKCNDCGKTFSQ[p. FSQISSLVY,KTFSQISSL,QISSLVYHR,ISSLVYHRR,TFSQISSL CLL M423I]ISSLVYHRRLHTGEKPYKCEECD V,SQISSLVYH,KTFSQISSLV,SQISSLVYHR,QISSLVYHRR,TF EAF SQISSLVY,GKTFSQISSL ZNF845 c.2774G>A p.R925H AHLACHHRIHTGEKPYKCNECGKTF[p. KTFHHNSVL,GKTFHHNSV,FHHNSVLVI,KTFHHNSVLV,TF PRAD R925H]HHNSVLVIHKTIHTGEKPYKCN HHNSVLVI,CGKTFHHNSV,HHNSVLVIHK,GKTFHHNSVL,F ECGK HHNSVLVIH ZNF880 c.1217A>G p.Q406R ECKECGKVFRHKFCLTNHHRMHTGE[p. HHRMHTGER,HRMHTGERPY KIRC Q406R]RPYKCNECGKAFRDCSGLTAHL LIHT ZP3 c.1085_108 p.V362fs VMSQWSRSASRNRRHVTEEADVTVG[p. EEADVTVGA,EEADVTVGAT,TEEADVTVGA KIRC 6insG V362fs]ATDLPGQEG* ZPBP c.460C>T p.R154C NFEESMSGIYTCFLEYKPTVEEIVK[p.R1 IVKCLQLKY,CLQLKYAIY,EEIVKCLQL,CLQLKYAIYA,IVKCLQ GBM 54C]CLQLKYAIYAYREPHYYYQFTARYH LKYA,KCLQLKYAIY,VEEIVKCLQL A ZSCAN18 c.674_675 p.P225fs SSILSDGVYERHMDPLLLPGELASP[p.P WSWGDPGTF,LASPQPGPW,SPQPGPWSW,GELASPQPG STAD insC 225fs]QPGPWSWGDPGTF* ZSWIM2 c.641C>A p.S214Y TSMLKCPLCRKEFAPLKLILEEFKN[p.S2 KNYSKLVAA,LILEEFKNY,FKNYSKLVA,EEFKNYSKL,ILEEFK LUAD 14Y]YSKLVAAAEKERLDKHLGIPCNNCK NYSK,YSKLVAAAEK,KNYSKLVAAA,KLILEEFKNY,FKNYSKL Q VAA,LEEFKNYSKL,EEFKNYSKLV ZSWIM4 c.1219G>A p.E407K GPSLQPTMAPAPELLQKGSTCITNT[p.E GSTCITNTK,TKGWVGHPL,KGSTCITNT,NTKGWVGHPL CESC 407K]KGWVGHPLDPIGCLCRALLEACR LEE ZSWIM6 c.1829de|A p.Q610fs LAIAIVNTLRRQQQKQLEMFRTQKK[p. RTQKKSYPI,TQKKSYPIK,MFRTQKKSY,RTQKKSYPIK,EMFR KICH Q610fs]SYPIKT* TQKKSY,FRTQKKSYPI ZZEF1 c.89T>C p.V30A PSHSSEDEAAAAGGEGWGPHQDWAA GPHQDWAAA,WAAASGTTPG ACC [p.V30A]ASGTTPGPGVAAPALPPAAAL LEPAR ZZZ3 c.14G>A p.R5Q MAAS[p.R5Q]QSTRVTRSTVGLNGLDE MAASQSTRV,ASQSTRVTR,SQSTRVTRST HNSC SFCGRTLRN ZZZ3 c.485G>A p.R162Q IKSDKESVEQRSTWDNDADFQGTK[p. KQACRCLIL,GTKQACRCLI,DFQGTKQACR,TKQACRCLIL LUSC R162Q]QACRCLILDDCEKREIKKVNVSE EGP

Example 5

Recurrent Mutations for Cancer Subtype Specific Immunogenic Compositions.

The Cancer Genome Atlas (TCGA) contains comprehensive large-scale genome sequencing data from tumor samples to catalogue genetic mutations responsible for cancer. Tumor-specific neoantigenic peptides for use in an immunogenic composition can be selected based on a number of criteria. The first criteria is based on gene expression. The fraction of patients (per tumor type) who express the gene at >10 transcripts per million was determined. Estimates assume a random assortment of HLA type vs. mutation status of each gene vs. gene expression (per tumor type). National yearly incidence was used to quantify the population that could be treated with each peptide. Peptides were ranked by expected population. The results of the analysis is shown in Table 9.

TABLE 9  Mutant Sequence (SEQ Relevant Tumor Presenting ID NOS 33503-33732 Estimated Types HLAs respectively, in Yearly (>500 patients (predicted Mutation order of appearance) Population per year) <500 nm) RBM14 p.AAAAAAA286del VTAASTSYY 19282 Pancreatic Cancer HLA.A01.01 (uc009yrj.2) HLA.A03.01 HLA.A11.01 HLA.A26.01 HLA.A26.02 HLA.A26.03 HLA.A29.02 HLA.A68.01 HLA.A80.01 HLA.B15.01 HLA.B15.03 HLA.B15.17 HLA.B58.01 HRAS p.G12D (uc001lpv.2) KLVVVGADGV 16466 Colorectal Cancer HLA.A02.01 KRAS p.G12D (uc001rgp.1) Pancreatic Cancer HLA.A02.03 NRAS p.G12D (uc009wgu.2) Uterine Corpus HLA.A02.06 Endometrial Carcinoma NRAS p.G12V (uc009wgu.2) KLVVVC-3AVGV 13995 Colorectal Cancer HLA.A02.01 KRAS p.G12V (uc001rgp.1) Lung HLA.A02.03 Adenocarcinorna HLA.A02.06 Pancreatic Cancer Uterine Corpus Endometrial Carcinoma NRAS p.G12V (uc009wgu.2) VVGAVGVGK 11278 Colorectal Cancer HLA.A03.01 KRAS p.G12V (uc001rgp.1) Lung HLA.A11.01 Pancreatic Cancer Adenocarcinorna Uterine Corpus Endometrial Carcinoma KRAS p.G12C (uc001rgp.1) KLVVVGACGV 7538 Colorectal Cancer HLA.A02.01 NRAS p.G12C (uc009wgu.2) Lung HLA.A02.03 HRAS p.G12C (uc001lpv.2) Adenocarcinoma HLA.A02.06 KRAS p.G12C (uc001rgp.1) VVGACGVGK 5751 Colorectal Cancer HLA.A03.01 NRAS p.G12C (uc009wgu.2) Lung HLA.A11.01 HRAS p.G12C (uc001lpv.2) Adenocarcinoma NRAS p.G12V (uc009wgu.2) VVVGAVGVGK 5535 Colorectal Cancer HLA.A11.01 KRAS p.G12V (uc001rgp.1) Lung HLA.A68.01 Adenocarcinoma Pancreatic Cancer TP53 p.R248W (uc002gim.2) GMNWRPILTI 5006 Breast Cancer HLA.A02.01 Colorectal Cancer HLA.A02.03 Pancreatic Cancer PIK3CA p.E542K (uc003fjk.2) AISTRDPLSK 4852 Bladder Cancer HLA.A03.01 Breast Cancer HLA.A11.01 FRG1B p.110T (uc010ztl.1) KLSDSRTAL 4782 Prostate Cancer HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.B07.02 HLA.B15.03 GATA3 p.H435fs (uc001ijz.2) KI fV1FATLQR 4535 Breast Cancer HLA.A03.01 HLA.A11.01 HLA.A30.01 HLA.A31.01 HLA.A68.01 HRAS p.G12D (uc001lpv.2) VVGADGVGK 4530 Colorectal Cancer HLA.A11.01 KRAS p.G12D (uc001rgp.1) Pancreatic ancer NRAS p.G12D (uc009wgu.2) NRAS p.Q61R (uc009wgu.2) ILDTAG REEY 4433 Melanoma HLA.A01.01 KRAS p.Q61R (uc001rgp.1) Thyroid Cancer HRAS p.Q61R (uc001lpv.2) NRAS p.Q61K (uc009wgu.2) ILDTAGKEEY 4203 Colorectal Cancer HLA.A01.01 HRAS p.Q61K (uc001lpv.2) Melanoma KRAS p.Q61K (uc001rgp.1) GATA3 p.H435fs (uc001ijz.2) MLTGPPARV 4113 Breast Cancer HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 HLA.A68.02 HLA.A69.01 RBM47 p.495_502AAAAAAAA>A AAAAVIPTV 4035 Pancreatic Cancer HLA.A02.01 (uc003gvc.2) HLA.A02.02 HLA.A02.03 HLA.A02.06 HLA.A68.02 HLA.A69.01 HLA.B15.17 RBM47 p.495_502AAAAAAAA>A AAAAAVIPTV 3864 Pancreatic Cancer HLA.A02.01 (uc003gvc.2) HLA.A02.03 HLA.A02.06 HLA.A68.02 GATA3 p.H435fs (uc001ijz,2) YMFLKAESK 3832 Breast Cancer HLA.A03.01 HLA.A11.01 HLA.A68.01 GATA3 p.H435fs (uc001ijz.2) SMLTGPPARV 3718 Breast Cancer HLA.A02.01 HLA.A02.03 HLA.A02.06 GATA3 p.H435fs (uc001ijz.2) YIVIFLKAESKI 3718 Breast Cancer HLA.A02.01 HLA.A02.03 HLA.A02.06 GATA3 p.H435fs (uc001ijz.2) TLQRSSLWCL 3621 Breast Cancer HLA.A02.01 HLA.A02.03 AP3S1 p.K41fs (uc003krl.2) LVSEMKMIN 3603 Pancreatic Cancer HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 HLA.A68.02 HLA.A69.01 PIK3CA p.H1047R (uc003fjk.2) FMKQMNDAR 3582 Breast Cancer HLA.A31.01 HLA.A33.01 HLA.A68.01 KRAS p.Q61L (uc001rgp.1) LLDILDTAGL 3563 Colorectal Cancer HLA.A02.01 NRAS p.Q61L (uc009wgu.2) Lung HLA.A02.03 HRAS p.Q61L (uc001lpv.2) Adenocarcinoma HLA.A02.06 Melanoma GATA3 p.H435fs (uc001ijz.2) FATLQRSSL 3551 Breast Cancer HLA.B07.02 HLA.B08.01 HLA.B39.01 AP3S1 p.K41fs (uc003krl.2) HINSEMKMFV 3524 Pancreatic Cancer HLA.A02.01 HLA.A02.03 HLA.A02.06 HLA.A68.02 FRG1B p.L52S (uc010ztl.1) ALSASNSCH 3502 Prostate Cancer HLA.A02.01 HLA.A02.03 HLA.A02.06 FRG1B p.L52S (uc010ztl.1) FQNGKMALSA 3502 Prostate Cancer HLA.A02.01 HLA.A02.03 HLA.A02.06 RBM14 p.AAAAAAA286del AVTAASTSY 3477 Pancreatic Cancer HLA.A26.02 (uc009yrj.2) HLA.A29.02 HLA.615.01 HLA.B15.03 HLA.B15.17 KRAS p.G12R (ruc001rgp.1) VVGARGVGK 3176 Pancreatic Cancer HLA.A03.01 NRAS p.G12R (uc009wgu.2) HLA.A11.01 PIK3CA p.E545K (uc003fjk.2) SEITKQEKDF 3090 Breast Cancer HLA.B44.02 FRG1B p.A53T (uc010ztl.1) LLTSNSCFI 3016 Prostate Cancer HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 FRG1B p.A53T (uc010ztl.1) ALLTSNSCH 2959 Prostate Cancer HLA.A02.01 HLA.A02.03 HLA.A02.06 FRG1B p.I10T (uc010ztl.1) RTALKSGYGK 2787 Prostate Cancer HLA.A03.01 HLA.A11.01 HLA.A68.01 FRG1B p.A50P (uc010ztl.1) FQNGKMPLL 2781 Prostate Cancer HLA.A02.01 Melanoma HLA.A02.02 HLA.A02.03 HLA.A02.06 HLA.B15.03 HLA.B39.01 PIK3CA p.H1047L (uc003fik.2) FMKQMNDAL 2610 Breast Cancer HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 HLA.B08.01 HLA.B15.01 HLA.B15.03 KRAS p.Q61L (uc001rgp.1) ILDTAGLEEY 2555 Colorectal Cancer HLA.A01.01 NRAS p.Q61L (uc009wgu.2) Lung HRAS p.Q61L (uc001lpv.2) Adenocarcinoma Melanoma FRG1B p.A113 (uc010ztl.1) ITLKSGYGIK 2523 Prostate Cancer HLA.A03.01 Melanoma HLA.A11.01 HLA.A30.01 HLA.A31.01 HLA.A68.01 ANAPC1 p.T537A (uc002thi.2) VSAPKPLSK 2521 Pancreatic Cancer HLA.A03.01 Prostate Cancer HLA.A11.01 HLA.A30.01 GATA3 p.H435fs (uc001ijz.2) FLKAESKIIVI 2496 Breast Cancer HLA.A02.03 HLA.B08.01 HLA.B15.01 HLA.B15.03 FRG1B p.A50P (uc010ztl.1) FQNGKMPLLA 2486 Prostate Cancer HLA.A02.01 Melanoma HLA.A02.03 HLA.A02.06 PIK3CA p.H1047R (uc003fik.2) YFIVIKQMNDAR 2478 Breast Cancer HLA.A33.01 HLA.A68.01 GATA3 p.S408fs (uc001ijz.2) AIQPVLWTT 2371 Breast Cancer HLA.A02.01 HLA.A02.02 HLA.A02.06 RBM1.4 p.AAAAAAA286del AVTAASTSYY 2363 Pancreatic Cancer HLA.A11.01 (uc009yrj.2) FRG1B p.110T (uc010ztl.1) KLSDSRTALK 2356 Prostate Cancer HLA.A03.01 HLA.A11.01 FRG1B p.A11T (uc010ztl.1) KLSDSRITL 2328 Prostate Cancer HLA.A02.01 Melanoma HLA.A02.02 HLA.A02.03 HLA.A02.06 HLA.B15.03 ANAPC1 p.T537A uc002thi.2) GVSAPKPLSK 2260 Pancreatic Cancer HLA.A03.01 Prostate Cancer HLA.A11.01 TP53 p.Y220C (uc002gim.2) VVVPCEPPEV 2200 Breast Cancer HLA.A02.01 HLA.A02.06 TP53 p.R248W (uc002gim.2) SSCMGGMNWR 2135 Colorectal Cancer HLA.A11.01 HLA.A68.01 KRAS p.G12R (uc001rgp.1) GARGVGKSAL 2075 Pancreatic Cancer HLA.B07.02 NRAS p.G12R (uc009wgu.2) RAC1 p.P29S (uc003spx.2) TTNAFSGEY 2042 Melanoma HLA.A01.01 HLA.A11.01 HLA.A25.01 HLA.A26.01 HLA.A26.02 HLA.A26.03 HLA.A29.02 HLA.A68.01 HLA.A80.01 HLA.B15.01 HLA.B15.03 HLA.B15.17 GATA3 p.H435fs (uc001ijz.2) GPPARVPAV 2039 Breast Cancer HLA.B07.02 GATA3 p.H435fs (uc001ijz.2) KPKRDGYMF 2039 Breast Cancer HLA.B07.02 GATA3 p.H435fs (uc001ijz.2) KPKRDGYMEL 2039 Breast Cancer HLA.B07.02 KRAS p.G12A (uc001rgp.1) KLVVVGAAGV 2034 Colorectal Cancer HLA.A02.01 HRAS p.G12A (uc001lpv.2) Lung HLA.A02.03 NRAS p.G12A (uc009wgu.2) Adenocarcinoma HLA.A02.06 SPOP p.F133L (uc002ipg.2) FVQGKDWGL 2002 Prostate Cancer HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 HLA.A68.02 HLA.A69.01 GATA3 p.H435fs (uc001ijz.2) CSMLTGPPAR 1995 Breast Cancer HLA.A11.01 HLA.A33.01 HLA.A68.01 WASH3P p.G175S (uc002cdi.2) SIRAAGGISK 1978 Prostate Cancer HLA.A03.01 WASH2P p.G175S (uc002tkh.2) Melanoma HLA.A11.01 ARFGAP3 p.N299fs (uc003bdd.2) EIAEVLFHI 1959 Prostate Cancer HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 HLA.A26.02 HLA.A26.03 HLA.A68.02 HLA.A69.01 GATA3 p.S408fs (uc001ijz.2) ALQPLQPHA 1906 Breast Cancer HLA.A02.01 HLA.A02.02 HLA.A02.03 ARFGAP3 p.N299fs (uc003bdd.2) SAWDLEIAEV 1892 Prostate Cancer HLA.A02.01 HLA.A02.06 HLA.A68.02 FRG1B p.I59V (uc010ztl.1) LLASNSCFV 1824 Prostate Cancer HLA.A02.01 FRG1 p.I157V (uc003izs.2) Melanoma HLA.A02.02 HLA.A02.03 HLA.A02.06 HLA.A68.02 HLA.A69.01 ARFGAP3 p.N299fs (uc003bdd.2) KMLTQTDSA 1818 Prostate Cancer HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 PTH2 p.L22del (uc002pnn.1) LLLLLLLLV 1807 Prostate Cancer HLA.A02.01 CTSA p.L37del (uc002xqh.2) HLA.A02.02 AGPAT2 p.17_18insL (uc004cii.1) HLA.A02.03 HLA.A02.06 TP53 p.R2480 (uc002gim.2) SSCMGGMNQR 1795 Bladder Cancer HLA.A11.01 HLA.A68.01 KRAS p.G12(2 (uc001rgp.1) VVVGACGVGK 1785 Colorectal Cancer HLA.A11.01 NRAS p.G12C (uc009wgu.2) Lung HRAS p.G12C (uc001lpv.2) Adenocarcinorna PiK3CA p.N345K (uc003fjk.2) KILCATYVK 1776 Breast Cancer HLA.A03.01 HLA.A11.01 HLA.A30.01 HLA.A31.01 FRG1B p.A11T (uc010ztl.1) KLSDSRITLK 1749 Prostate Cancer HLA.A03.01 HLA.A11.01 FRG1B p.A11T (uc010ztl.1) RITLKSGYGK 1749 Prostate Cancer HLA.A03.01 HLA.A11.01 GATA3 p.H435fs (uca11ijz.2) AVPFDLHFCR 1749 Breast Cancer HLA.A11.01 HLA.A68.01 PIK3CA p.E542K (uc003fjk.2) ISTRDPLSK 1746 Breast Cancer HLA.A11.01 TP53 p.G245S (uc002gim.2) SSCMGSMNR 1732 Colorectal Cancer HLA.A11.01 HLA.A31.01 HLA.A68.01 GATA3 p.H435fs (uca11ijz.2) AESKIMFATL 1731 Breast Cancer HLA.B40.01 HLA.B44.02 AKT1 p.E17K (uc001ypk.2) WLHKRGKYIK 1717 Breast Cancer HLA.A03.01 AKT2 p.E17K (uc002onf.2) PIK3CA p.N345K (uc003fjk.2) ILCATYVKV 1715 Breast Cancer HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 FRG1B p.I59V (uc010ztl.1) ALLASNSCFV 1698 Prostate Cancer HLA.A02.01 FRG1 p.I157V (uc003izs.2) Melanoma HLA.A02.03 HLA.A02.06 FRG1B p.L52S (uc010ztl.1) SASNSCFIR 1685 Prostate Cancer HLA.A11.01 HLA.A31.01 HLA.A33.01 HLA.A68.01 PIK3CA p.N345K (uc003fjk.2) KILCATYVKV 1679 Breast Cancer HLA.A02.01 HLA.A02.03 HLA.A02.06 AP3S1 p.K41fs (uc003krl.2) ETFHLVSEM 1635 Pancreatic Cancer HLA.A25.01 HLA.A26.01 HLA.A26.02 HLA.A26.03 HLA.A68.01 HLA.A68.02 HLA.A69.01 HLA.B15.17 PIK3CA p.N345K (uc003fik.2) KVNIRDIDK 1620 Breast Cancer HLA.A03.01 HLA.A11.01 HLA.A30.01 KRAS p.G12A (uc00irgp.1) VVGAAGVGK 1613 Colorectal Cancer HLA.A03.01 HRAS p.G12A (uc001lpv.2) Lung HLA.A11.01 NRAS p.G12A (uc009wgu.2) Adenocarcinoma CDC27 p.D555E (uc002ile.3) TLWHLOKEV 1577 Colorectal Cancer HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 GATA3 p.H435fs (uc00lijz.2) ESKIMFATL 1573 Breast Cancer HLA.A68.02 HLA.B08.01 TP53 p.P75fs (uc002gim.2) KPTRAATVSV 1536 Colorectal Cancer HLA.B07.02 CTNNB1 p.T41A (uc010hla.1) ATAPSLSGK 1536 Prostate Cancer HLA.A03.01 HLA.A11.01 HLA.A30.01 HLA.A31.01 HLA.A68.01 CDC27 p.D555E (uc002ile.3) HLQKEVALSV 1530 Colorectal Cancer HLA.A02.01 HLA.A02.03 HLA.A02.06 PIK3CA p.H1047L (uc003fik.2) ALHGGWTTK 1513 Breast Cancer HLA.A03.01 HLA.A11.01 HLA.A30.01 UBC p.R73L (uc002gyy.3) RLRGGMOIFV 1474 Prostate Cancer HLA.A02.01 HLA.A02.03 HLA.A02.06 PEX1 p.1370fs (uc003uly.2) KMRRPVCYK 1456 Prostate Cancer HLA.A03.01 HLA.A11.01 HLA.A30.01 TP53 p.C238Y (uc002gim.2) TTIHYNYMY 1454 Colorectal Cancer HLA.A31.01 HLA.A01.01 HLA.A11.01 HLA.A25.01 HLA.A26.01 HLA.A26.02 HLA.A26.03 HLA.A29.02 HLA.A68.01 HLA.A80.01 HLA.B15.17 ANAPC1 p.T537A (uc002thi.2) APKPLSKLL 1449 Pancreatic Cancer HLA.B07.02 HLA.A11.01 HLA.A31.01 FRG1B p.A53T (uc010ztl.1) LTSNSCFIR 1447 Prostate Cancer HLA.A33.01 HLA.A68.01 RNF43 p.G659fs (uc002iwf.2) TQLARFFPI 1442 Colorectal Cancer HLA.A02.01 Prostate Cancer HLA.A02.02 HLA.A02.03 HLA.A02.06 HLA.A23.01 HLA.A30.01 HLA.A31.01 HLA.A69.01 HLA.B08.01 HLA.B08.03 HLA.B15.03 HLA.B38.01 HLA.B39.01 HLA.B40.01 HLA.B40.02 AP3S1 p.K41fs (uc003krl.2) EIFFILVSEMK 1440 Pancreatic Cancer HLA.A11.01 HLA.A68.01 PIK3CA p.H1047R (uc003fjk.2) ARHGGWTTK 1426 Breast Cancer HLA.B27.05 PIK3CA p.H1047R (uc003fjk.2) ARHGGWTTKM 1426 Breast Cancer HLA.B27.05 GATA3 p.S408fs (uc001ijz.2) QPVLWITPPL 1421 Breast Cancer HLA.B07.02 FRG1B p.A50P (uc010ztl.1) MPLLASNSCF 1374 Prostate Cancer HLA.B07.02 WASH3P p.G175S (uc002cdi.2) ISKAKLRSM 1337 Prostate Cancer HLA.A30.01 WASH2P p.G175S (uc002tkh.2) Melanoma HLA.B08.01 HLA.B15.17 HRAS p.G13R (uc001lpv.2) VVGAGRVGK 1324 Colorectal Cancer HLA.A03.01 NRAS p.G13R (uc009wgu.2) HLA.A11.01 HLA.A30.01 ACADS p.R330H (uc001tza.3) RLLTWHAAM 1321 Prostate Cancer HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 HLA.B08.01 HLA.B15.01 HLA.B15.03 HLA.B15.17 HRAS p.G12D (uc001lpv.2) LVVVGADGV 1284 Pancreatic Cancer HLA.A02.06 KRAS p.G12D (uc001rgp.1) HLA.A68.02 NRAS p.G12D (uc009wgu.2) HLA.A69.01 KRAS p.G12S (uc001rgp.1) KLVVVGASGV 1278 Colorectal Cancer HLA.A02.01 HRAS p.G12S (uc001lpv.2) HLA.A02.03 NRAS p.G12S (uc009wgu.2) HLA.A02.06 TP53 p.A159V (uc002gim.2) RVRVMAIYK 1271 Bladder Cancer HLA.A03.01 HLA.A11.01 HLA.A30.01 HLA.A31.01 HLA-A p.Q78R (uc003nol.2) IEREGPEYW 1271 Prostate Cancer HLA.B44.02 HLA.B44.03 GATA3 p.H435fs (uc001ijz.2) LORSSLWCL 1248 Breast Cancer HLA.A02.06 HLA.B15.01 HLA.B15.03 ZMIZ2 ALQEKOSCIEL 1226 Pancreatic Cancer HLA.A02.01 p.VAAAAATATATATAT153del HLA.A02.03 (uc003tlr.2) GIGYF2 p.Q1005del (uc002vtj.3) KLSGWGNVSK 1204 Pancreatic Cancer HLA.A03.01 HLA.A11.01 FRG1B p.L52S (uc010ztl.1) LSASNSCFIR 1190 Prostate Cancer HLA.A11.01 HLA.A68.01 AKT1 p.E17K (uc001ypk.2) WLHKRGKYI 1172 Breast Cancer HLA.A02.03 AKT2 p.E17K (uc002onf.2) HLA.B08.01 PEX1 p.I370fs (uc003uly.2) KLGQIIMKK 1165 Prostate Cancer HLA.A03.01 HLA.A11.01 RAC1 p.P295 (uc003spx.2) FSG EYI PTV 1152 Melanoma HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 HLA.A68.02 HLA.A69.01 GATA3 p.H435fs (uc001ijz.2) IMKPKRDGY 1151 Breast Cancer HLA.B15.01 HLA.B15.03 AEBP1 p.K1133del (uc003tkb.2) EEEIATGOAF 1143 Pancreatic Cancer HLA.B44.02 HLA.A03.01 FBXW7 p.R465H (uc003ims.2) TVHCMHLHEK 1142 Colorectal Cancer HLA.A11.01 HLA.A68.01 TSPAN4 p.L92V (uc001lsd.1) LTFFLLLLV 1140 Prostate Cancer HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 HLA.A68.02 HLA.A69.01 HLA.B15.17 TP53 p.R158L (uc002gim.2) RVLAMAIYK 1136 Lung Squamous HLA.A03.01 Cell Carcinoma HLA.A11.01 HLA.A30.01 HLA.A31.01 HLA.A68.01 NRAS p.G12V (uc009wgu.2) LVVVGAVGV 1130 Pancreatic Cancer HLA.A02.03 KRAS p.G12V (uc001rgp.1) HLA.A02.06 HLA.A68.02 HLA.A69.01 GATA3 p.S408fs (uc00lijz.2) HMSSLSHISA 1127 Breast Cancer HLA.A02.01 HLA.A02.03 HLA.A02.06 CTNNB1 p.S37F (uc010hia.1) YLDSGIHFG 1121 Uterine Corpus HLA.A02.01 Endometrial HLA.A02.02 Carcinoma HLA.A02.06 CTNNB1 p.S37F (uc010hia.1) YLDSGIHFGA 1120 Uterine Corpus HLA.A02.01 Endometrial HLA.A02.03 Carcinoma HLA.A02.06 CTNNB1 p.537C (uc010hia.1) YLDSGIHCGA 1111 Uterine Corpus HLA.A02.01 Endometrial HLA.A02.03 Carcinoma HLA.A02.06 SF3B1 p.K700E (uc002uue.2) GLVDEQQEV 1099 Breast Cancer HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 KRAS p.012R (uc001rgp.1) VVVGARGVGK 1082 Pancreatic Cancer HLA.A11.01 NRAS p.G12R (uc009wgu.2) EGFR p.L858R (uc003tqk.2) KITDFGRAK 1054 Lung HLA.A03.01 Adenocarcinoma HLA.A11.01 HLA.A30.01 TP53 p.E271K (uc002gim.2) NLLGRNSFK 1046 Bladder Cancer HLA.A03.01 HLA.A11.01 HLA.A68.01 TSPAN4 p192V (uc001lsd.1) FLLLLVVFL 1044 Prostate Cancer HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 TSPAN4 p.L92V (uc001lsd.1) LLVVELLEA 1044 Prostate Cancer HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 TSPAN4 p.L92V (uc001lsd.1) LLLLVVFLL 1030 Prostate Cancer HLA.A02.01 HLA.A02.02 HLA.A02.06 TSPAN4 p.L92V (uc001lsd.1) FLLLLVVFLL 1027 Prostate Cancer HLA.A02.01 HLA.A02.03 HLA.A02.06 TSPAN4 p.L92V (uc001lsd.1) LLLVVFLLEA 1027 Prostate Cancer HLA.A02.01 HLA.A02.03 HLA.A02.06 TSPAN4 p.L92V (uc001lsd.1) LLTFFLLLLV 1027 Prostate Cancer HLA.A02.01 HLA.A02.03 HLA.A02.06 ARFGAP3 p.N299fs (uc003bdd.2) LEIAEVLFHI 1024 Prostate Cancer HLA.B40.01 HLA.B44.02 FRG1B p.I10T (uc010ztl.1) TALKSGYGK 1020 Prostate Cancer HLA.A11.01 HLA.A68.01 RBM14 p.AAAAAAA286del ATAAAVTAA 1020 Pancreatic Cancer HLA.A02.02 (uc009yrj.2) HLA.A02.03 HLA.A02.06 HLA.A68.02 HLA.A69.01 KRAS p.G12S (uc001rgp.1) VVGASGVG K 1019 Colorectal Cancer HLA.A03.01 HRAS p.G12S (uc001lpv.2) HLA.A11.01 NRAS p.G12S (uc009wgu.2) UBC p.L149R (uc002gyy.3) STLHLVLRR 1014 Prostate Cancer HLA.A11.01 HLA.A31.01 HLA.A33.01 HLA.A68.01 PIK3CA p.N345K (uc003fjk.2) ATYV KV N IR 1007 Breast Cancer HLA.A11.01 HLA.A31.01 HLA.A33.01 HLA.A68.01 ERBB3 p.V104M (uc001sjh.2) RMVRETOVY 990 Colorectal Cancer HLA.A03.01 HLA.A29.02 HLA.A80.01 HLA.B15.01 HLA.B15.03 HLA.B15.17 GATA3 p.H435fs (uc001ijz.2) AESKIMFAT 984 Breast Cancer HLA.B40.01 HLA.B40.02 HLA.B45.01 FRG1B p.L52S (uc01ztl.1) ALSASNSCF 982 Prostate Cancer HLA.B15.01 HLA.B15.03 TP53 p.E271K (uc002gim.2) LLGRNSFKV 978 Bladder Cancer HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 TP53 p.E271K (uc002gim.2) NLLGRNSFKV 969 Bladder Cancer HLA.A02.01 HLA.A02.03 HLA.A02.06 FRG1B p.A11T (uc010ztl.1) TLKSGYGKY 969 Prostate Cancer HLA.A26.02 HLA.A29.02 HLA.B15.01 HLA.B15.03 NFE2L2 p.E79Q (uc002ulh.3) QLDEQTGEFL 966 Lung Squamous HLA.A02.01 Cell Carcinoma HLA.A02.06 TP53 p.K132N (uc002gim.2) ALNNMFCQL 955 Bladder Cancer HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 HLA.B15.01 HLA.B15.03 MAP2K1 p.P124S (uc010bhq.2) NSSYIVGFY 943 Melanoma HLA.A01.01 HLA.A26.01 HLA.A26.02 HLA.A29.02 HLA.A68.01 HLA.A80.01 HLA.B15.03 HLA.B15.17 TSPAN9 p.S50L (uc001qlp.2) ATESPSFPL 937 Melanoma HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 HLA.A11.01 HLA.A30.01 HLA.A31.01 HLA.A68.02 HLA.A69.01 HLA.B15.03 HLA.B15.17 HLA.B58.01 SF361 p.K700E (uc002uue.2) QEVRTISAL 936 Breast Cancer HLA.B15.03 HLA.B39.01 HLA.B40.01 HLA.B40.02 HLA.B44.02 HLA.B44.03 ZNF91 p.R333H (uc002nre.2) FSHSSTLAK 907 Prostate Cancer HLA.A03.01 HLA.A11.01 HLA.A30.01 HLA.A68.01 FNBP4 p.TT58del (uc009ylv.2) APSAATTTA 905 Prostate Cancer HLA.B07.02 FNBP4 p.TT58del (uc009ylv.2) APSAATTTVA 905 Prostate Cancer HLA.B07.02 RAC1 p.P29S (uc003spx.2) YTTNAFSGEY 901 Melanoma HLA.A01.01 HLA.A68.01 ACADS p.R330H (uc001tza.3) LTWHAAMLK 896 Prostate Cancer HLA.A03.01 HLA.A11.01 HLA.A30.01 HLA.A31.01 HLA.A68.01 TP53 p.C242F (uc002gim.2) SSFMGGMNR 889 Lung Squamous HLA.A03.01 Cell Carcinoma HLA.A11.01 HLA.A31.01 HLA.A33.01 HLA.A68.01 CNPY3 p.17_18LL>L (uc003ota.3) LLLLPAPEL 878 Prostate Cancer HLA.A02.01 HLA.A02.02 HLA.A02.06 CNPY3 p.17_18LL>L (uc003ota.3) LLLLLLLLPA 876 Prostate Cancer HLA.A02.01 HLA.A02.03 HLA.A02.06 CNPY3 p.17_1811>L (uc003ota.3) LLLLLLLPA 876 Prostate Cancer HLA.A02.01 HLA.A02.03 HLA.A02.06 CNPY3 p.17_18LL>L (uc003ota.3) LLLLLPAPEL 876 Prostate Cancer HLA.A02.01 HLA.A02.03 HLA.A02.06 ZMIZ2 AAAAAVAAL 855 Pancreatic Cancer HLA.A02.02 p.VAAAAATATATATAT153del HLA.A02.03 (uc003tlr.2) HLA.A02.06 HLA.A68.02 HLA.B07.02 HLA.B15.03 HLA.B15.17 PODXL p.28_30PSP>P SPSPSQNAT 852 Prostate Cancer HLA.B07.02 (uc003vqw.3) PODXL p.2830PSP>P SPSQNATQTT 852 Prostate Cancer HLA.B07.02 (uc003vqw.3) AP3S1 p.K41fs (uc003krl.2) HLVSEMKMF 849 Pancreatic Cancer HLA.A26.02 HLA.B15.01 HLA.B15.03 STK19 p.D89N (uc003nyv.2) NPIFRFSSL 849 Melanoma HLA.A26.02 HLA.B07.02 HLA.B08.01 HLA.B39.01 NUF2 p.S340L (uc001gcq.1) NLFKRLMIV 845 Colorectal Cancer HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 HLA.B08.01 FRG1B p.A53T (uc010ztl.1) ALLTSNSCF 833 Prostate Cancer HLA.B15.01 HLA.B15.03 UBC p.L149R (uc002gyy.3) LVLRRRGGM 829 Prostate Cancer HLA.B08.01 TP53 p.A159P (uc002gim.2) RVRPMAIYK 820 Lung HLA.A03.01 Adenocarcinoma HLA.A11.01 HLA.A30.01 HLA.A31.01 HLA.A68.01 FRG1B p.K13N (uc010ztl.1) IALNSGYGK 791 Prostate Cancer HLA.A03.01 HLA.A11.01 HLA.A30.01 HLA.A31.01 HLA.A68.01 GATA3 p.H435fs (uc001ijz.2) VPFDLHFCR 791 Breast Cancer HLA.A33.01 HLA.A68.01 UBC p.L149R (uc002gyy.3) STI.HLVL.RRR 789 Prostate Cancer HLA.A11.01 HLA.A33.01 HLA.A68.01 ACADS p.R330H (uc001tza.3) LLTWHAAML 789 Prostate Cancer HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 GATA3 p.H435fs (uc001ijz.2) ATLQRSSLW 782 Breast Cancer HLA.B15.17 HLA.B57.01 HLA.B58.01 MAP2K1 p.P1245 (uc010bhq.2) VLHECNSSYI 779 Melanoma HLA.A02.01 HLA.A02.03 HLA.A02.06 ACADS p.R330H (uc001tza.3) RLLTVVHAAML 773 Prostate Cancer HLA.A02.01 HLA.A02.03 HLA.A02.06 RXRA p.S427F (uc004cfb.2) RLPALRFIGL 771 Bladder Cancer HLA.A02.01 RXRG p.S428F (uc001gda.2) HLA.A02.03 HLA.A02.06 ERBB3 p.V104M (uc001sjh.2) LPLPNLRMV 765 Colorectal Cancer HLA.B07.02 TSPAN9 p.S50L (uc001qlp.2) LLSAANLVI 759 Melanoma HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.B15.01 HLA.B15.03 HLA.B15.17 CINNB1 p.S33F (uc010hia.1) YLDI-GIHSGA 755 Uterine Corpus HLA.A02.01 Endometrial HLA.A02.03 Carcinoma HLA.A02.06 CTNNB1 p.S33F (uc010hia.1) YLDFGIHSG 754 Uterine Corpus HLA.A02.01 Endornetrial HLA.A02.02 Carcinoma HLA.A02.06 PTEN p.R130G (uc001kfb.2) GTGVMICAY 751 Uterine Corpus HLA.A29.02 Endometrial HLA.B15.01 Carcinoma HLA.B15.17 RXRA p.S427F (uc004cfb.2) LPALRFIGL 748 Bladder Cancer HLA.B07.02 RXRG p.S428F (uc001gda.2) HLA.B08.01 NOTCH2 p.P6fs (uc001eik.2) WIPALRRSAV 747 Bladder Cancer HLA.B07.02 HLA.B08.01 JMY p.PPPPPPPPPPPP811del LPPTPPPLPV 733 Pancreatic Cancer HLA.B07.02 (uc003kfx.3) JMY p.PPPPPPPPPPPP811del SPLPPTPPPL 733 Pancreatic Cancer HLA.B07.02 (uc003kfx.3) ACADS p.R330H (uc001tza.3) LLTWHAAMLK 729 Prostate Cancer HLA.A03.01 HLA.A11.01 HLA.A68.01 GATA3 p.H435fs (uc001ijz.2) RSSIMKPKR 703 Breast Cancer HLA.A30.01 HLA.A31.01 OGEOD1 p.G477fs (uc002ejb.2) FL.LLTLPKV 702 Pancreatic Cancer HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 HERC2P3 p.A803V (uc001ytg.2) RVRDIVI KO. M 699 Pancreatic Cancer HLA.A30.01 HLA.B07.02 HLA.B15.17 C1QB ESGDYKATQK 697 Pancreatic Cancer HLA.A68.01 p.GPKGPMGPKGGPGAPGAP9Odel (uc001bgd.2) SLC38A10 p.1071_1072II>I GLNPLPDVQV 689 Pancreatic Cancer HLA.A02.01 (uc002jzz.1) HLA.A02.03 UBB p.I188fs (uc002gpx.2) IPPTSRGSSL 686 Prostate Cancer HLA. B07.02 UBC p.I191T (uc002gyy.3) UBB p.I188fs (uc002gpx.2) PPTSRGSSL 686 Prostate Cancer HLA. B07.02 UBC p.I191T (uc002gyy.3) CTNNB1 p.D32N (uc010hia.1) YLNSG1HSGA 672 Uterine Corpus HLA.A02.01 Endornetrial HLA.A02.03 Carcinoma HLA.A02.06 FRG1B p.K13N (uc010ztl.1) ALNSGYGKYL 670 Prostate Cancer HLA.A02.01 HLA.A02.03 NBPF14 p.R25C (uc001eqf.2) KLCPQLAENK 667 Pancreatic Cancer HLA.A03.01 HLA.A11.01 IARS2 p.R832C (uc001hmc.2) VIVCSFAPI 662 Melanoma HLA.A02.01 HLA.A02.02 HLA.A02.03 HLA.A02.06 HLA.A68.02 HLA.A69.01 HLA.B15.03 P1K3CA p.H1047R (uc003fjk.2) KONINDARHG 661 Breast Cancer HLA.B15.03 CTNNB1 p.D32N (uc010hia.1) YLNSGIHSG 658 Uterine Corpus HLA.A027.01 Endometrial HLA.A02.02 Carcinoma HLA.A02.03 SIK3 p.950_951QQ>Q (uc001ppy.2) QEYQELFRHM 653 Pancreatic Cancer HLA.B40.01 HLA.B44.02 IARS2 p.R832C (uc001hmc.2) ILDVIVCSFA 651 Melanoma HLA.A02.01 HLA.A02.03 HLA.A02.06 AP3S1 p.K41fs (uc003krl.2) RETFHLVSEM 650 Pancreatic Cancer HLA.B40.01 PPP2R1A p.P179R (uc002pyp.2) RMVRRAAASK 649 Uterine Corpus HLA.A03.01 Endometrial Carcinoma HLA.A11.01 ZMIZ2 AAAAAAVAAL 641 Pancreatic Cancer HLA.B07.02 p.VAAAAATATATATAT153del (uc003tlr.2) HSD17B7P2 p.N175S (uc010qex.1) SARKSNFSL 637 Prostate Cancer HLA.A30.01 HLA.B07.02 HLA.B08.01 HLA.B15.17 ARL16 p.G6R (uc002kbf.2) RVAGRRALSR 632 Melanoma HLA.A03.01 HLA.A11.01 HLA.A33.01 HLA.A68.01 GATA3 p.S408fs (uc001ijz.2) TIPPLOHGHR 623 Breast Cancer HLA.A33.01 HLA.A68.01 AP3S1 p.K4ifs (uc003krl.2) FHLVSEMKM 619 Pancreatic Cancer HLA.B38.01 HLA.B39.01 PLEKHA6 p.V328fs (uc001hau.2) SIMIVISWMPPL 613 Colorectal Cancer HLA.A02.01 HLA.A02.03 HLA.A02.06 HLA.A68.02 HLA.B07.02 LZTS1 KLEGLELEV 609 Pancreatic Cancer HLA.A02.01 p.RTQDLEGALRTKGLEL432del HLA.A02.02 (uc003wzr.2) HLA.A02.03 HLA.A02.06 HSD17B7P2 p.N175S (uc010qex.1) WTSSRSARK 607 Prostate Cancer HLA.A03.01 HLA.A11.01 HLA.A30.01 HLA.A68.01 RBM14 p.AAAAAAA286del GAAATAAAV 606 Pancreatic Cancer HLA.A02.03 (uc009yrj.2) HLA.A68.02 TP53 p.R249M (uc002gim.2) MPILTIITL 606 Lung HLA.A69.01 Adenocarcinorna HLA.B07.02 HLA.B08.01 HLA.B15.03 HLA.B39.01 HLA.B53.01 IRF2BPL p.114_115QQ>Q QLNHVDGSSK 605 Prostate Cancer HLA.A03.01 (uc001xsy.2) HLA.A11.01 POLI p.D17del (uc002lfj.3) EEDAEAWAM 599 Prostate Cancer HLA.B40.01 HLA.B44.02 HLA.B44.03 ZNF780A p.Q600H (uc010xvh.1) HMHURHO,K 594 Prostate Cancer HLA.A03.01 HLA.A11.01 HLA.A30.01 HLA.A31.01 HLA.A33.01 HLA.A58.01 FRG1B p.I10T (uc010ztI.1) LSDSRTALK 589 Prostate Cancer HLA.A11.01 PARG p.A584T (uc001jih.2) EETEAQHLY 585 Prostate Cancer HLA.B44.02 HLA.B44.03 GATA3 p.S408fs (uc001ijz.2) SSLSHISAL 573 Breast Cancer HLA.A02.06 HLA.B08.01 HLA.B15.03 HLA.B15.17 HLA.B39.01 EGFR p.L858R (uc003tkq.2) FGRAKLLGA 564 Lung HLA.B08.01 Adenocarcinorna TP53 p.R249M (uc002gim.2) RMPILTIITL 563 Lung HLA.A02.01 Adenocarcinorna HLA.A02.03 HLA.A02.06 PARG p.A584T (uc001jih.2) TEAQHLYQSI 557 Prostate Cancer HLA.B40.01 HLA.B44.02 CDC27 p.D555E (uc002ile.3) EVALSVLSK 557 Colorectal Cancer HLA.A11.01 HLA.A68.01 GATA3 p.H435fs (uc001ijz.2) MFLKAESKI 554 Breast Cancer HLA.A23.01 FRG1B p.K13N (uc010ztl.1) RIALNSGYGK 546 Prostate Cancer HLA.A03.01 HLA.A11.01 CTNNB1 p.G34R (uc010hia.1) YLDSRIHSGA 530 Uterine Corpus HLA.A02.01 Endornetrial HLA.A02.03 Carcinoma HLA.A02.06 FRG1B p.L525 (uc010zt1.1) LSASNSCH 528 Prostate Cancer HLA.A68.02 HLA.B15.17 HLA.B58.01 AXIN2 p.W663fs (uc002jfi,2) TPAPPPVPT 520 Colorectal Cancer HLA.B07.02 AXIN2 p.W663fs (uc002jfi.2) VPTCSPRTL 520 Colorectal Cancer HLA.B07.02 FCGBP p.A2493V (uc002omp.3) RPGLHRFVV 504 Pancreatic Cancer HLA.B07.02 HLA.B08.01

Example 6

Therapeutic Targeting of Recurrent Mutations Expressed in Genes Containing Extracellular Domains.

Tumor-specific mutations present in greater than 1% of a population of cancer patients may be targeted with a drug or therapy that recognizes the tumor-specific neoepitope resulting from the mutation. The mutation is preferably within an extracellular domain. The drug or therapy is an antibody, antibody fragment, antibody drug conjugate, aptamer, CAR, or T cell receptor. The antibody or fragment thereof may be humanized, fully humanized, or chimeric. The antibody fragment may be a nanobody, Fab, Fab′, (Fab′)2, Fv, ScFv, diabody, triabody, tetrabody, Bis-scFv, minibody, Fab2, or Fab3 fragment.

A recurrent mutation that may be targeted is FGFR3:p.S249C. Fibroblast growth factor receptor 3 (FGFR3) is a protein that in humans is encoded by the FGFR3 gene. FGFR3 has also been designated as CD333 (cluster of differentiation 333). The full-length protein includes an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The mutation occurs in the extracellular domain of the protein. The mutation is present in 6.92% of bladder cancer (BLCA) patients analyzed and 1.12% of lung squamous cell carcinoma (LUSC) patients analyzed.

Another recurrent mutation that may be targeted is ERBB3:p.V104M. Receptor tyrosine-protein kinase erbB-3, also known as HER3 (human epidermal growth factor receptor 3), is a membrane bound protein that in humans is encoded by the ERBB3 gene. ErbB3 is a member of the epidermal growth factor receptor (EGFR/ERBB) family of receptor tyrosine kinases. The mutation is present in 1.72% of colorectal cancer (CRC), 2.86% of colon adenocarcinoma (COAD), 2.42% of stomach adenocarcinoma (STAD), and 2.06% of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) patients analyzed.

Another recurrent mutation that may be targeted is EGFR:p.L858R. The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is the cell-surface receptor for members of the epidermal growth factor family (EGF-family) of extracellular protein ligands. The mutation is present in 3.24% of lung adenocarcinoma (LUAD) patients analyzed.

Another recurrent mutation that may be targeted is MUC4:p.H4205Q, Mucin 4 (MUC 4) is a mucin protein that in humans is encoded by the MUC4 gene. This gene encodes an integral membrane glycoprotein found on the cell surface, although secreted isoforms may exist. The mutation is present in 2.3% of prostate adenocarcinoma (PRAD), 2.31% of bladder urothelial carcinoma (BLCA), and 7.14% of uterine carcinosarcoma (UCS) patients analyzed.

Another recurrent mutation that may be targeted is PDGFRA:p.R483fs. Platelet-derived growth factor receptor, alpha polypeptide is a protein that in humans is encoded by the PDGFRA gene. This gene encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. The mutation is present in 1.92% of prostate adenocarcinoma (PRAD) patients analyzed.

Another recurrent mutation that may be targeted is TMEM52 23_26LLPL>L. Transmembrane protein 52 is encoded by the TMEM52 gene. The mutation is present in 1.53% of prostate adenocarcinoma (PRAD) patients analyzed.

Another recurrent mutation that may be targeted is PODXL 28_30PSP>P. Podocalyxin-like protein 1 is a protein that in humans is encoded by the PODXL gene. The mutation is present in 1.53% of prostate adenocarcinoma (PRAD), 15.56% of adrenocortical carcinoma (ACC), and 3.57% of uterine carcinosarcoma (UCS) patients analyzed.

Having thus described in detail preferred embodiments of the present invention, it is to be understood that the invention defined by the above paragraphs is not to be limited to particular details set forth in the above description as many apparent variations thereof are possible without departing from the spirit or scope of the present invention. 

What is claimed is:
 1. A method of treating cancer in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising: (i) a polypeptide comprising at least one amino acid sequence comprising at least 8 contiguous amino acids of: PPLQHGHRHGLEPCSMLTGPPARVPAVPFDLHFCRSSIMKPKRDGYMFLKAES KIMFATLQRSSLWCLCSNH (residues 26-97 of SEQ ID NO: 1297); or (ii) a nucleic acid encoding the polypeptide; and a pharmaceutically acceptable carrier.
 2. The method of claim 1, wherein the at least 8 contiguous amino acids binds to an HLA protein in the subject.
 3. The method of claim 1, wherein the polypeptide comprises at least two distinct amino acid sequences.
 4. The method of claim 3, wherein the polypeptide comprises at most 20 distinct amino acid sequences.
 5. The method of claim 1, wherein the polypeptide is from 8 to 50 amino acids in length.
 6. The method of claim 1, wherein the at least 8 contiguous amino acids binds to a protein expressed by an HLA-A, HLA-B or HLA-C allele of the subject with a KD of less than 500 nM.
 7. The method of claim 1, wherein the pharmaceutical composition is an immunogenic composition or a vaccine composition.
 8. The method of claim 7, wherein the pharmaceutical composition further comprises an immunomodulator or adjuvant.
 9. The method of claim 8, wherein the immunomodulator or adjuvant is poly(I:C).
 10. The method of claim 1, further comprising administering an additional cancer therapy to the subject.
 11. The method of claim 10, wherein the additional therapy is a checkpoint inhibitor; or wherein the additional therapy is surgery, chemotherapy, a targeted therapy, or a combination thereof.
 12. The method of claim 1, wherein the cancer is breast cancer.
 13. The method of claim 1, wherein the subject has a GATA3 frameshift mutation.
 14. The method of claim 13, wherein the GATA3 frameshift mutation is a GATA3:p.H434 frameshift mutation.
 15. The method of claim 12, wherein the breast cancer is non-metastatic breast cancer.
 16. The method of claim 12, wherein the breast cancer is metastatic breast cancer.
 17. The method of claim 12, wherein the breast cancer is HER-2-positive breast cancer.
 18. The method of claim 12, wherein the breast cancer is a stage I breast cancer, stage II breast cancer, stage IIA breast cancer or operable stage IIC breast cancer.
 19. The method of claim 1, wherein the polypeptide comprises an amino acid sequence ESKIMFATL (SEQ ID NOs: 13457, 13526, 13595, 13661, 13717, 13772, 33585).
 20. The method of claim 1, wherein the polypeptide comprises an amino acid sequence FATLQRSSL (SEQ ID NOs: 13454, 13523, 13592, 13658, 13714, 13769, 33527).
 21. The method of claim 1, wherein the polypeptide comprises an amino acid sequence FLKAESKIM (SEQ ID NOs: 13438, 13507, 13576, 13643, 13700, 13754, 33542).
 22. The method of claim 1, wherein the polypeptide comprises an amino acid sequence FLKAESKIMF (SEQ ID NOs: 13488, 13559, 13628, 13687, 13741, 13796).
 23. The method of claim 1, wherein the polypeptide comprises an amino acid sequence GPPARVPAV (SEQ ID NOs: 13452, 13521, 13590, 13656, 13712, 13767, 33554).
 24. The method of claim 1, wherein the polypeptide comprises an amino acid sequence IMKPKRDGYM (SEQ ID NOs: 13477, 13548, 13617, 13679, 13734, 13789).
 25. The method of claim 1, wherein the polypeptide comprises an amino acid sequence KIMFATLQR (SEQ ID NOs: 13441, 13510, 13579, 13646, 13703, 13757, 33513).
 26. The method of claim 1, wherein the polypeptide comprises an amino acid sequence KPKRDGYMF (SEQ ID NOs: 13453, 13522, 13591, 13657, 13713, 13768, 33555).
 27. The method of claim 1, wherein the polypeptide comprises an amino acid sequence KPKRDGYMFL (SEQ ID NOs: 13485, 13556, 13625, 13684, 13738, 13793, 33556).
 28. The method of claim 1, wherein the polypeptide comprises an amino acid sequence LHFCRSSIM (SEQ ID NOs: 13456, 13525, 13594, 13660, 13716, 13771).
 29. The method of claim 1, wherein the polypeptide comprises an amino acid sequence MFATLQRSSL (SEQ ID NOs: 13487, 13558, 13627, 13686, 13740, 13795).
 30. The method of claim 1, wherein the polypeptide comprises an amino acid sequence MFLKAESKI (SEQ ID NOs: 13444, 13513, 13582, 13649, 13706, 13760, 33726).
 31. The method of claim 1, wherein the polypeptide comprises an amino acid sequence MLTGPPARV (SEQ ID NOs: 13437, 13506, 13575, 13642, 13699, 13753, 33517).
 32. The method of claim 1, wherein the polypeptide comprises an amino acid sequence SMLTGPPARV (SEQ ID NOs: 13471, 13541, 13610, 13672, 13728, 13783, 33521).
 33. The method of claim 1, wherein the polypeptide comprises an amino acid sequence TLQRSSLWCL (SEQ ID NOs: 13473, 13543, 13612, 13674, 13730, 13785, 33523).
 34. The method of claim 1, wherein the polypeptide comprises an amino acid sequence YMFLKAESK (SEQ ID NOs: 13440, 13509, 13578, 13645, 13702, 13756, 33520).
 35. The method of claim 1, wherein the polypeptide comprises an amino acid sequence YMFLKAESKI (SEQ ID NOs: 13472, 13542, 13611, 13673, 13729, 13784, 33522). 